Clinical, immunological, molecular and therapeutic
findings in monogenic immune dysregulation diseases:
Middle East and North Africa registry

Mahnaz Jamee, Gholamreza Azizi, Safa Baris, Elif Karakoc-Aydiner, Ahmet

Ozen, Sara Ş Kiliç, Hulya Kose, Zahra Chavoshzadeh, Seyed Alireza

Mahdaviani, Tooba Momen, et al.

► To cite this version:

Mahnaz Jamee, Gholamreza Azizi, Safa Baris, Elif Karakoc-Aydiner, Ahmet Ozen, et al. Clinical, immunological, molecular and therapeutic findings in monogenic immune dysregulation diseases: Middle East and North Africa registry. Clinical Immunology, 2022, 244, pp.109131. 10.1016/j.clim.2022.109131. pasteur-05017977

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Clinical, immunological, molecular and therapeutic findings in monogenic immune dysregulation diseases: Middle East and North Africa registry

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Mahnaz Jamee<sup>a, b</sup>, Gholamreza Azizi<sup>c, d, 1, **</sup>, Safa Baris<sup>e, f, g</sup>, Elif Karakoc-Aydiner<sup>e, f, g</sup>, Ahmet Ozen<sup>e, f, g</sup>, Sara Ş. Kiliç<sup>h</sup>, Hulya Kose<sup>h</sup>, Zahra Chavoshzadeh<sup>i</sup>, Seyed Alireza Mahdaviani<sup>j</sup>, Tooba Momen<sup>k</sup>, Bibi Shahin Shamsian<sup>l</sup>, Mazdak Fallahi<sup>i</sup>, Samin Sharafian<sup>i</sup>, Nesrin Gülez<sup>m</sup>, Ayşe Aygun<sup>n</sup>, Neslihan Edeer Karaca<sup>n</sup>, Necil Kutukculer<sup>n</sup>, Nashat Al Sukait<sup>o</sup>, Tariq Al Farsi<sup>o</sup>, Salem Al-Tamemi<sup>p</sup>, Nisreen Khalifa<sup>q</sup>, Reda Shereen<sup>r</sup>, Dalia El-Ghoneimy<sup>r</sup>, Rasha El-Owaidy<sup>r</sup>, Nesrine Radwan<sup>r</sup>, Raed Alzyoud<sup>s</sup>, Mohamed-Ridha Barbouche<sup>t</sup>, Imen Ben-Mustapha<sup>u</sup>, Najla Mekki<sup>u</sup>, Afef Rais<sup>u</sup>, Rachida Boukari<sup>v</sup>, Reda Belbouab<sup>v</sup>, Kamel Djenouhat<sup>w</sup>, Azzeddine Tahiat<sup>w</sup>, Souad Touri<sup>x</sup>, Gehad Elghazali<sup>y</sup>, Suleiman Al-Hammadi<sup>z</sup>, Hiba Mohammed Shendi<sup>aa</sup>, Amna Alkuwaiti<sup>aa</sup>, Brahim Belaid<sup>ab</sup>, Reda Djidjik<sup>ab</sup>, Hasibe Artac<sup>ac</sup>, Mehdi Adeli<sup>ad</sup>, Ali Sobh<sup>ae</sup>, Marwa H. Elnagdy<sup>ae</sup>, Sara A. Bahgat<sup>ae</sup>, Gulnara Nasrullayeva<sup>af</sup>, Janet Chou<sup>ag</sup>, Nima Rezaei<sup>ah</sup>, Waleed Al-Herz<sup>ai, aj</sup>, Raif S. Geha<sup>ag</sup>, Hassan Abolhassani<sup>a, ak, al, *, 1</sup>, MENA-I. E. I. Study Group

**Abbreviations:** AIHA, Autoimmune hemolytic anemia; CBC, Complete cell blood count; CD, Cluster of differentiation; CID, Combined immunodeficiency; CMV, Cytomegalovirus; COVID-19, Coronavirus disease; CTLA-4, Cytotoxic T-lymphocyte-associated protein 4; CVID, Common variable immunodeficiency; DNT, Double negative T; EBV, Epstein-Barr virus; ESID, European Society for Immunodeficiencies; GOF, Gain of function; GvHD, Graft-versus-host-disease; HLH, Hemophagocytic lymphohistiocytosis; HSCT, hematopoietic stem cell transplantation; IBD, Inflammatory bowel disease; IEI, Inborn error of immunity; Ig, Immunoglobulin; IL, Interleukin; IQR, Interquartile range; ITP, idiopathic thrombocytopenic purpura; IUIS, International Union of Immunological Societies; IgRT, immunoglobulin replacement therapy; JAK, Janus kinase; LRBA, LPS Responsive Beige-Like Anchor; MENA, Middle East and North Africa; MIDD, Monogenic immune dysregulation diseases; NK, Natural killer; RTI, Respiratory tract infection; STAT, Signal transducer and activator of transcription; Th, T helper; Tregs, Regulatory T cells.

* Correspondence to: H. Abolhassani, Division of Clinical Immunology, Department of Biosciences and Nutrition, NEO, Blickagangen 16, Karolinska Institute, Stockholm SE-14157, Sweden.

** Correspondence to: G. Azizi, Non-communicable Diseases Research Center, Vice Chancellor for Research, Alborz University of Medical Sciences, Karaj, Iran.
E-mail addresses: azizi@abzums.ac.ir (G. Azizi), hassan.abolhassani@ki.se (H. Abolhassani).

<footnote><sup>a</sup> Immunology and Allergy Department, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran</footnote>

<footnote><sup>b</sup> Pediatric Nephrology Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran</footnote>

<footnote><sup>c</sup> Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran</footnote>

<footnote><sup>d</sup> Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran</footnote>

<footnote><sup>e</sup> Marmara University School of Medicine, Division of Allergy and Immunology, Istanbul, Turkey</footnote>

<footnote><sup>f</sup> The Isil Berat Barlan Center for Translational Medicine, Marmara University School of Medicine, İstanbul, Turkey</footnote>

<footnote><sup>g</sup> Istanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, Turkey</footnote>

<footnote><sup>h</sup> Division of Pediatric Allergy and Immunology, Department of Pediatrics, Uludag University, Faculty of Medicine, Bursa, Turkey</footnote>

<footnote><sup>i</sup> Immunology and Allergy Department, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran</footnote>

<footnote><sup>j</sup> Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran</footnote>

<footnote><sup>k</sup> Department of Asthma, Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute of Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran</footnote>

<footnote><sup>l</sup> Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran</footnote>

<footnote><sup>m</sup> Division of Pediatric Allergy and Immunology, University of Health Sciences, Dr. Behcet Uz Children's Education and Research Hospital, Izmir, Turkey</footnote>

<footnote><sup>n</sup> Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey</footnote>

<footnote><sup>o</sup> Department of Pediatric Allergy and Clinical Immunology, The Royal Hospital, Muscat, Oman</footnote>

<footnote><sup>p</sup> Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman</footnote>

<footnote><sup>q</sup> NBK Children's Hospital, Kuwait City, Kuwait</footnote>

<footnote><sup>r</sup> The pediatric allergy immunology and rheumatology unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt</footnote>

<footnote><sup>s</sup> Allergy, Immunology, and Rheumatology, Queen Rania Children's Hospital, Amman, Jordan</footnote>

<footnote><sup>t</sup> Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia</footnote>
ᵃ Laboratory of Transmission, Control and Immunobiology of Infections (LR11IPT02), Department of Immunology, Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia

ᵇ Department of Pediatrics, University Hospital of Mustapha Pacha, Algiers, Algeria

ᶜ Laboratory of Immunology, Department of Medical Biology, Rouiba Hospital, University of Algiers, Algiers, Algeria

ᵈ Department of Pediatrics, University Hospital of Blida, Blida, Algeria

ᵉ Department of Immunology, Sheikh Khalifa Medical City- Union 71/Purehealth, and Faculty of Medicine, United Arab Emirates University, Al Ain, United Arab Emirates

ᵉ⁾ College of Medicine, Mohammed Bin Rashid University for Medicine and Health Sciences, Dubai, United Arab Emirates

ᵃᵃ Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates

ᵇᵃ Department of Medical Immunology, University Hospital Center of Beni Messous, University of Algiers, Algiers, Algeria

ᶜᵃ Division of Immunology and Allergy, Department of Pediatrics, Selmek University Faculty of Medicine, Konya, Turkey

ᵈᵃ Allergy and Immunology Division, Pediatrics Department, Sidra Medicine, Doha, Qatar

ᵉᵃ Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt

ᵃᵃ Department of Immunology Research Laboratory, Azerbaijan Medical University, Baku, Azerbaijan

ᵇᵃ Division of Immunology, Boston Children's Hospital and Harvard Medical School, 1 Blackfan Circle, Karp, Building, Boston, Massachusetts, USA

ᶜᵃ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

ᵃ¹ Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait City, Kuwait

ᵃ¹ Allergy and Clinical Immunology Unit, Pediatric Department, Al-Sabah Hospital, Kuwait City, Kuwait

ᶜᵃ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

ᵃ¹ Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden

## ARTICLE INFO

### Keywords:

- Inborn errors of immunity
- Primary immunodeficiency
- Immune dysregulation
- Autoimmune disorders
- Lymphoproliferation
- Genetic

## ABSTRACT

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42–192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD.

## 1. Introduction

Monogenic immune dysregulation diseases (MIDD), also referred to as primary immune regulatory disorders, are a growing number of inborn errors of immunity (IEIs) caused by pathogenic genetic variants clustered in different pathways of over-activated adaptive immunity or/ and defective immune tolerance [1]. Affected patients may exhibit traditional symptoms of IEIs (i.e., recurrent severe infections); however, the clinical phenotype is usually dominated by autoimmune disorders, hyper-inflammation, lymphoproliferation, malignancy, and/or amplified atopy [2]. Symptoms of immune dysregulation are not confined to MIDDs and may manifest in various severity in other IEIs, most frequently in combined immunodeficiency (CID), common variable immunodeficiency (CVID), and autoinflammatory disorders [3,4]. Therefore, MIDD patients may be labeled with an incorrect initial IEI diagnosis, leading to consequent mismanagement [5]. In addition, these symptoms are not usually present at birth and may manifest variably due to the different underlying pathological mechanisms, incomplete penetration and variable expressivity, and probably different epigenetic modifiers [6], contributing to significant diagnostic delay and worse prognosis. In recent years, the diagnosis of MIDDs has been facilitated by developments in cellular and molecular immunology, including next-generation sequencing [1]. In addition, novel precision medicine strategies are tailored to revert immune dysregulation complications, such as the application of soluble CTLA4 fusion protein, anti-CD20, and sirolimus in LRBA deficiency and CTLA4 haploinsufficiency, as well as JAK-inhibitors in STAT3 or STAT1 gain-of-function [7–9].

The Middle East and North Africa region (MENA) populations are of different ethnic origins. The high consanguineous marriage rates (with frequencies ranging between 20 and 50%), coupled with the large family size in some communities, results in an increased prevalence of autosomal recessive MIDDs [10]. In the most recent single- or multi-center

available studies from MENA countries, MIDD had a mean frequency of 8.5% (2.6% in Iran [11], 4.3% in UAE [12], 6.2% in Algeria [13], 8.6% in Qatar [14], 9.4% in Oman [15], 13.6% in Egypt [16], 15% in Kuwait [17]) among all registered IEIs, which is higher than the reported global prevalence for MIDD in the latest survey by Jeffrey Modell Centers Network (4875 of 135,410, 3.6%) [18]. Studies of IEI in the MENA region had contributed to the discovery and understanding of several novel monogenic immunodeficiency disorders [10,19]. Particularly, the diagnosis and treatment of MIDDs are both a challenge in countries of the MENA region, where access to diagnostic tools and the therapeutic setting is limited due to financial and infrastructure restrictions. Compared to other developed countries, MIDDs diagnosis in the MENA region is also hampered by the lack of knowledge among primary physicians regarding IEI and the lack of advanced diagnostic tests and targeted treatment in some countries [10].

We sought to evaluate the clinical, immunological, and molecular aspects of patients with MIDDs originating from the MENA region to increase knowledge on the prevalence and spectrum of MIDDs and further investigate their natural history, genetic pattern, and treatment outcome.

## 2. Materials and methods

### 2.1. Study design

A total of 17,120 patients with IEI were reported in the MENA registry from participating 22 countries in 2021, of which 516 patients (~3%) had a clinical diagnosis of immune dysregulation [19]. To have a more comprehensive investigation of monogenic patients with immune dysregulation as well, this retrospective longitudinal study was conducted between August 2021 and April 2022 among countries of the MENA registry to analyze the clinical, immunologic, molecular, and
therapeutic data of only patients with identified monogenic defects. After establishing a research agreement with centers from MENA countries, the survey was conducted by primary physicians and investigators selected by each center. The study was approved by the ethics committee of Alborz University of Medical Science, Karaj, Iran (Approval code: IR.ABZUMS.REC.1400.165), according to the guidelines of the Helsinki declaration.

## 2.2. Study population

All patients with monogenic diseases of immune dysregulation were enrolled in the study. The inclusion criteria included: a. established clinical diagnosis of diseases of immune dysregulation according to the criteria of the European Society for Immunodeficiency (ESID) registry working party [20]. b. the presence of a definite genetic study showing pathogenic defects in one of the 47 genes implicated in immune dysregulation according to table IV of the latest International Union of Immunological Societies (IUIS) classification [21,22] and American College of Medical Genetics and Genomics (ACMG) criteria [23]. c. origination of patients from one of the countries in the MENA region. The exclusion criteria included: a. clinical diagnosis of MIDDs with no genetic confirmation, b. significant incomplete documentation of demographic, clinical, or immunological features. c. digenic or oligogenic defects.

## 2.3. Data acquisition

Data of eligible patients were collected through a questionnaire encrypted by a Microsoft Excel spreadsheet to collect demographic data, medical history, physical examination, and laboratory and molecular findings. Demographic data included sex, ethnicity, consanguinity, age at last visit, age at disease onset and diagnosis, delay of diagnosis, family history of IEI and/or autoimmunity, and current life status. Laboratory data composed of complete cell blood count (CBC), T-and B-cell counts, serum levels of immunoglobulins, and other advanced diagnostic immunologic tests including the frequency of T helper 17 (Th17), regulatory T cells (Tregs), CD21lowB cell, and CD3$^+$CD4$^+$CD8$^-$ double-negative (DN) T cells, cytokine levels, and lymphocyte transformation/cytotoxicity test. Additional evaluations included bone marrow biopsy (mainly for the diagnosis of hemophagocytic lymphohistiocytosis, HLH), hair shaft examination (for hypopigmentation diseases), virologic tests (mainly for detection of Epstein-Barr virus, EBV), lipid profile and other metabolic tests mainly ferritin and vitamin B12 [20]. Data related to therapeutic modalities such as immunoglobulin replacement therapy (IgRT), biologic or immunosuppressive drugs, and hematopoietic stem cell transplantation (HSCT) was also gathered. After receiving data from each center, two investigators assessed the completed questionnaires. In case of ambiguity in terms of entered data or inclusion criteria, the corresponding center was contacted. Based on the identified mutation, patients were classified in one of the main 8 subcategories of MIDDs based on IUIS [21,22] including familial HLH, HLH with hypopigmentation, EBV susceptibility with HLH, EBV susceptibility without HLH, syndromes with autoimmunity with high DNT cells but without Tregs defect, syndromes with autoimmunity and normal DNT and Tregs, syndromes with autoimmunity and Tregs defect but normal DNT cells, and immune dysregulation with colitis.

## 2.4. Statistical analyses

For the patients' collected data, identification numbers were assigned and data were transferred to the SPSS statistical software version 26 (v. 26.0, Chicago, IL) and R statistical systems (version 3.4.1., R Foundation for Statistical Computing, Vienna, Austria). For quantitative variables with abnormal distribution, median and interquartile range (IQR), and for qualitative variables, frequency and percentages were calculated. A descriptive data analysis was performed for

quantitative data. The statistical correlations between two or more groups were determined using the Chi-square test or Fischer exact test, and the Mann-Whitney test or Kruskal-Wallis test. The Kaplan-Meier survival estimator was used to assess overall survival or to compare mortality rates among different groups of MIDDs. P-values less than 0.05 were considered statistically significant.

## 3. Results

This study included 343 patients with 42% females from eleven countries of the MENA region: Iran (106, 30.9%), Turkey (81, 23.6%), Kuwait (38, 11.1%), Oman (31, 9.0%), Algeria (20, 5.8%), Egypt (17, 5.0%), United Arab Emirates (UAE, 17, 5.0%), Tunisia (13, 3.8%), Jordan (12, 3.5%), Qatar (6, 1.7%), and Azerbaijan (2, 0.6%) (Fig. 1). The median (IQR) age at presentation was 12.0 (3.0–41.3) months. The median (IQR) diagnostic delay was 24.0 (4.0–61.0) months. The majority of patients (83.1%) initially presented in the first 5 years of age. Parental consanguinity was reported in 76.0% of patients. The most common subgroups of IEIs based on the IUIS classification included syndromes with autoimmunity and Tregs defect but normal DNT cells (35%), and HLH with hypopigmentation (19.8%) while syndromes with autoimmunity and normal DNT and Tregs (5.5%) were the least common (Table 1).

As shown in Fig. 2, the most prevalent first presentations of immunodeficiency in all patients were respiratory tract infections (23.9%), autoimmunity (18.6%), organomegaly (13.3%), and chronic diarrhea (13.3%). The clinical manifestations of MIDD patients are presented in Table 2. The most common manifestations were infections, reported in 75.1% of patients (87.2% in syndromes with autoimmunity and Tregs defect but normal DNT cells), followed by lymphoproliferation in 53.8% of patients (77.8% in familial HLH), autoimmunity in 41% of patients (77.3% in syndromes with autoimmunity with high DNT cells but without Tregs defect), and atopy in 18.7% of patients (24.8% in syndromes with autoimmunity and Tregs defect but normal DNT cells). Malignancies were recorded in 26 patients (7.5%) mainly in the form of non-Hodgkin lymphoma (9 (2.9%) patients demonstrated EBV-associated lymphoma). Infection with EBV and Cytomegalovirus (CMV) was evident in 38 (12.4%) and 26 (8.5%) patients. The lowest frequency and diversity of non-infectious complications were observed in Immune dysregulation with colitis with the earliest onset of infections at 3 (1.0–5.2) months among all MIDDs (Table 2 and Fig. S1).

A summary of laboratory and immunologic findings is represented in Table 3. Among patients with available data, the predominant patterns of immunologic abnormality were as follows: lymphopenia in 63 (23.6%) patients (median (IQR) lymphocyte count: 2320 (735–4975) cells /µL), neutropenia in 74 (28%) (median (IQR) neutrophil count: 1985 (146.8–4270) cells /µL), thrombocytopenia in 79 (29%) (median (IQR) platelet count: 234 (119–346.5) cells /µL), anemia in 153 (54.1%) (median (IQR) hemoglobin count: 11 (8.8–12.8) g/dL), low CD3$^+$ T cells in 64 (26.6%) (median (IQR) % of CD3$^+$ T cell: 71 (62–78.4)), low CD4$^+$ T cells in 73 (30.3%) (median (IQR) % of CD4$^+$ T cell: 36.5 (29.2–43.4)), high CD8$^+$ T cells in 56 (23.5%) (median (IQR) % of CD8$^+$ T cell: 28.4 (22.1–39)), low CD19$^+$ B cells in 79 (34.1%) (median (IQR) % of CD19$^+$ T cell: 14.8 (6.2–22)), low NK cells in 27 (15.8%) (median (IQR) % of NK cell: 8 (4.8–11.9)), low IgG in 108 (42.2%) (median (IQR) IgG level: 645 (343–1150) mg/dL), low IgA in 97 (38.3%) (median (IQR) IgA level: 44.5 (12.5–112.3) mg/dL), low IgM in 87 (34.9%) (median (IQR) IgM level: 69.5 (27.8–130.5) mg/dL), high IgE in 31 (17%) (median (IQR) IgE level: 7 (1–29.8) IU/ml), low Th17 cells in 6 (42.9%) (median (IQR) % of Th17 cell: 0.5 (0.3–0.7)), low Tregs in 23 (67.6%) (median (IQR) % of Treg cell: 0.9 (0.3–2)), high DNT cells in 32 (49.2%) (median (IQR) % of DNT cell: 3.5 (1.3–7.6)), and high CD21low B cells in 15 (31.9%) (median (IQR) % of CD21low B cell: 3 (2–7.5)).

A pathogenic variant was identified in all 343 patients in whom mutations in 37 different genes were identified with LRBA (82, 23.9%), LYST (28, 8.2%), RAB27A (27, 7.9%), and FOXP3 (19, 5.5%) being the
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** An illustration of countries from MENA region and the prevalence and number of monogenic immune dysregulation diseases cases contributed to the study.</figcaption></figure>

most common genes mutated (Fig. 3). The gene variants in these patients consisted of 46.7% missense, 18% indel framshift, 13.8 large deletion, 11.4% splice site, and 10% stop-gain variants. Consistent with the high frequency of parental consanguinity in the cohort, an autosomal recessive pattern was observed in 77.3% of patients (Fig. 3). Treatment modalities included IgRT (132, 53%), HSCT (49, 14.3%), corticosteroids (139, 67.8%), immunosuppressives (126, 36.7%), and surgery (12, 3.5%). Prophylactic antimicrobials including anti-bacterial, anti-fungal, and anti-viral agents were prescribed for 119 (38.9%), 40 (13.1%), and 33 (10.8%) patients, respectively. The details of HSCTs are summarized in Table 4. Patients received HSCT at a median (IQR) age of 36 months (range 15.3–127.5) and were followed up for a median (IQR) period of 26.5 months (range 7.5–49.5). Most patients were HSC transplanted from a matched sibling donor (50%) or matched unrelated donor (18.2%) by bone marrow (79.1%), peripheral blood (11.6%), or cord blood (9.3%) stem cells. Twenty of the transplanted patients (40.8%) developed post-HSCT complications, mainly including graft-versus-host-disease (GvHD) (12, 24.5%), sepsis or CMV reactivation (7, 14.3%), and hemorrhagic/thrombotic events (5, 10.2%). HSCT was mainly prioritized for cases suffering from syndromes with autoimmunity and Tregs defect but normal DNT cells (18, 36.7%) and HLH with hypopigmentation (14, 28.6%). At the last follow-up, 29 (59.2% of) patients had survived the transplantation. No correlation was observed between age of transplantation and outcome (p = 0.141), however, Log Rank survival analysis showed the best survival for patients with bone marrow transplant source (p = 0.001) and matched sibling donor (p < 0.001).

The median (IQR) overall follow-up period for patients was 36 (10–75) months at the time of the study. Of note, 92 (30.9%) died due to IEI complications at a median age of 72 (36–138) months. Causes of mortality were available for 77 patients and included sepsis (23, 29.9%),

pneumonia (11, 14.3%), and HLH complications (9, 11.7%). The best and worst survival belonged to syndromes with autoimmunity and normal DNT and Tregs and HLH with hypopigmentation, respectively (Fig. 4). We then evaluated the impact of the severity of mutation within specific genetic defects that affected >10 patients with the same MIDD. There was a significantly lower survival in patients with FOXP3 deleterious mutations compared to missense variants (Fig. S2). To further evaluate the impact of HSCT on the survival of specific genetic mutations, we investigated MIDD with more than 2 transplanted patients. The most promising survival rate after HSCT was observed in patients with RAB27A deficiency (Fig. S3). In the following section, more detailed analyses of the demographic, clinical, immunological, and therapeutic findings in distinct MIDDs based on the IUIS category are presented.

## 3.1. HLH with hypopigmentation

Sixty-eight patients (19.8%) had defect in one of the *LYST* (28, 41.2%), *RAB27A* (27, 39.7%), *AP3B1* (8, 11.8%), or *AP3D1* (5, 7.4%) genes. Most patients belonged to Omani Arab (20, 29.4%), Turkish (16, 23.5%), and Persian (9, 13.2%) ethnic groups. The male: female ratio was 0.9. Patients had the lowest median (IQR) age [49 (25–117) months] at the time of study compared to other MIDD patients. The onset of atopy preceded other manifestations at a median age of 5 months, while infections, organomegaly, autoimmunity, and malignancy developed later at median ages of 11, 18, 28, and 110 months, respectively.

The median (IQR) diagnosis delay was 4 (0–30) months, which was the lowest among all MIDD categories, while the median (IQR) age at diagnosis was 24 (8–48) months.

First presentation was reported in 59 patients and included hair/skin color change (24, 40.7%), respiratory tract infections (RTIs, 13, 22%),
<table><caption>**Table 1**
Demographic data in patients with monogenic immune dysregulation diseases.</caption><thead><tr><th>Parameters</th><th>Total (n = 343)</th><th>HLH with hypopigmentation (n = 68)</th><th>fHLH (n = 28)</th><th>EBV susceptibility without HLH (n = 34)</th><th>EBV susceptibility with HLH (n = 20)</th><th>Syndromes with autoimmunity with high DNT cells but without Tregs defect (n = 22)</th><th>Syndromes with autoimmunity and normal DNT and Tregs cells (n = 19)</th><th>Syndromes with autoimmunity and Tregs defect but normal DNT cells (n = 120)</th><th>Immune dysregulation with colitis (n = 32)</th><th>p-value</th></tr></thead><tbody><tr><td>Sex, M/F (n = 342)</td><td>199 (58.2)/143 (41.8)</td><td>32 (47.1)/36 (52.9)</td><td>14 (50/14 (15))</td><td>17 (50)/17 (50)</td><td>14 (70)/6 (30)</td><td>15 (68.2)/7 (31.8)</td><td>12 (63.2)/7 (36.8)</td><td>76 (63.3)/44 (36.7)</td><td>19 (59.4)/13 (40.6)</td><td>0.311</td></tr><tr><td>Ethnicity (n = 343)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>&lt;0.001*</td></tr><tr><td>Persian, n (%)</td><td>104 (30.3)</td><td>9 (13.2)</td><td>3 (10.7)</td><td>8 (23.5)</td><td>12 (60)</td><td>2 (9.1)</td><td>8 (42.1)</td><td>47 (39.2)</td><td>15 (46.9)</td><td></td><td></td></tr><tr><td>Turkish, n (%)</td><td>81 (23.6)</td><td>16 (23.5)</td><td>4 (14.3)</td><td>18 (52.9)</td><td>1 (5)</td><td>1 (4.5)</td><td>5 (26.3)</td><td>32 (26.7)</td><td>4 (12.5)</td><td></td><td></td></tr><tr><td>Kuwaiti Arab, n (%)</td><td>38 (11.1)</td><td>7 (10.3)</td><td>8 (28.6)</td><td>6 (17.6)</td><td>1 (5)</td><td>4 (18.2)</td><td>4 (21.1)</td><td>4 (3.3)</td><td>4 (12.5)</td><td></td><td></td></tr><tr><td>Maghrebi Arab-Berber, n (%)</td><td>33 (9.6)</td><td>8 (11.8)</td><td>4 (14.3)</td><td>0</td><td>0</td><td>12 (54.5)</td><td>0</td><td>2 (1.7)</td><td>7 (21.9)</td><td></td><td></td></tr><tr><td>Omani Arab, n (%)</td><td>31 (9.0)</td><td>20 (29.4)</td><td>0</td><td>1 (2.9)</td><td>2 (10)</td><td>1 (4.5)</td><td>0</td><td>7 (5.8)</td><td>0</td><td></td><td></td></tr><tr><td>Egyptian Arab, n (%)</td><td>17 (5.0)</td><td>4 (5.9)</td><td>4 (14.3)</td><td>0</td><td>3 (15)</td><td>0</td><td>0</td><td>5 (4.2)</td><td>1 (3.1)</td><td></td><td></td></tr><tr><td>Emiratis Arab, n (%)</td><td>13 (3.8)</td><td>1 (1.5)</td><td>3 (10.7)</td><td>0</td><td>0</td><td>0</td><td>2 (10.5)</td><td>6 (5)</td><td>1 (3.1)</td><td></td><td></td></tr><tr><td>Jordanian Arab, n (%)</td><td>12 (3.5)</td><td>1 (1.5)</td><td>2 (7.1)</td><td>0</td><td>0</td><td>1 (4.5)</td><td>0</td><td>8 (6.7)</td><td>0</td><td></td><td></td></tr><tr><td>Caucasian, n (%)</td><td>6 (1.7)</td><td>0</td><td>3 (10.7)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>3 (2.5)</td><td>0</td><td></td><td></td></tr><tr><td>Azeri, n (%)</td><td>5 (1.5)</td><td>0</td><td>0</td><td>1 (2.9)</td><td>1 (5)</td><td>1 (4.5)</td><td>0</td><td>2 (1.7)</td><td>0</td><td></td><td></td></tr><tr><td>Others, n (%)</td><td>8 (2.3)</td><td>2 (2.9)</td><td>0</td><td>1 (2.9)</td><td>0</td><td>0</td><td>0</td><td>3 (2.5)</td><td>2 (6.3)</td><td></td><td></td></tr><tr><td>Age at study, month, median (IQR), (n = 307)</td><td>101 (42-192)</td><td>49 (25-117)</td><td>78 (6-179)</td><td>144 (67-208)</td><td>162 (56-270)</td><td>54 (29-163)</td><td>160 (96-225)</td><td>144 (77-228)</td><td>66 (38-126)</td><td>&lt;0.001*</td></tr><tr><td>Age at onset, month, median (IQR), (n = 325)</td><td>12 (3-39)</td><td>9 (2-23)</td><td>12 (1-91)</td><td>36 (4-90)</td><td>60 (6-96)</td><td>7 (3-14)</td><td>24 (3-36)</td><td>18 (7-48)</td><td>1 (1-2.5)</td><td>&lt;0.001*</td></tr><tr><td>Diagnosis delay, month, median (IQR), (n = 304)</td><td>24 (4-61)</td><td>4 (0-30)</td><td>4 (1-18)</td><td>48 (24-90)</td><td>24 (4-111)</td><td>10 (3-48)</td><td>27 (9-54)</td><td>37 (12-95)</td><td>12 (4-65)</td><td>&lt;0.001*</td></tr><tr><td>Age at diagnosis, month, median (IQR), (n = 311)</td><td>50 (18-120)</td><td>24 (8-48)</td><td>48 (3-107)</td><td>117 (49-163)</td><td>96 (34-162)</td><td>16 (10-56)</td><td>48 (23-87)</td><td>84 (34-144)</td><td>17 (4-66)</td><td>&lt;0.001*</td></tr><tr><td>Age at first infection, month, median (IQR), (n = 240)</td><td>14.5 (4-60)</td><td>11 (1.5-24)</td><td>6 (2-180)</td><td>36 (4-120)</td><td>72 (6-96)</td><td>8 (5-30)</td><td>12 (4-48)</td><td>30 (8-84)</td><td>3 (1-5)</td><td>&lt;0.001*</td></tr><tr><td>Age at first autoimmunity, month, median (IQR), (n = 137)</td><td>24 (6-84)</td><td>28 (5-84)</td><td>4 (3-100)</td><td>96 (2-122)</td><td>120</td><td>10 (6-42)</td><td>30 (15-48)</td><td>42 (11-99)</td><td>3 (1-12)</td><td>0.003*</td></tr><tr><td>Age at first organomegaly, month, median (IQR), (n = 147)</td><td>24 (6-72)</td><td>18 (2-33)</td><td>6 (3-62)</td><td>48 (8-153)</td><td>49 (7-84)</td><td>8 (4-14)</td><td>99</td><td>60 (18-120)</td><td>1</td><td>&lt;0.001*</td></tr><tr><td>Age at first malignancy, month, median (IQR), (n = 20)</td><td>121 (71-178)</td><td>110</td><td>96</td><td>122 (78-175)</td><td>102 (33-261)</td><td>180</td><td>-</td><td>146 (48-240)</td><td>-</td><td>0.893</td></tr><tr><td>Age at first atopy, month, median (IQR), (n = 50)</td><td>24 (6-84)</td><td>5 (1-14)</td><td>-</td><td>24 (6-72)</td><td>12</td><td>18 (3-69)</td><td>10 (3-22)</td><td>48 (15-123)</td><td>6</td><td>0.036*</td></tr><tr><td>Life status, D/A (n = 298)</td><td>92 (30.9)/206 (69.1)</td><td>31 (48.4)/33 (51.6)</td><td>6 (24)/19 (76)</td><td>7(21.9)/25 (78.1)</td><td>8 (44.4)/10 (55.6)</td><td>5 (35.7)/9 (64.3)</td><td>1 (5.6)/17 (94.4)</td><td>28 (27.7)/73 (72.3)</td><td>6(22.2)/21 (77.8)</td><td>0.005*</td></tr><tr><td>Age at death (n = 21)</td><td>72 (36-138)</td><td>52 (36-108)</td><td>1.3</td><td>144</td><td>167</td><td>80</td><td>-</td><td>99 (37-219)</td><td>25</td><td>0.174</td></tr></tbody></table>

M; male, F; female, D; dead, A; alive, IQR; interquartile range, HLH: Hemophagocytic lymphohistiocytosis, fHLH: familial HLH, EBV: Epstein-Barr virus, DNT: double negative T lymphocytes. The data were analyzed by Kruskal-Wallis test. * All ages are in month. * A p-value < 0.05 is considered as significant.
<figure><img src="image_4.png" /><figcaption>Fig. 2. The frequency of first presentations in monogenic immune dysregulation diseases patients. RTI; respiratory tract infection, FTT; failure to thrive.</figcaption></figure>

and organomegaly (7, 11.9%). The most common clinical manifestations were infections (44, 67.7%) [mainly lower RTIs (LRTI, 23, 35.4%) and upper RTIs (URTI, 13, 20%)] and lymphoproliferation (28, 43.1%) [splenomegaly (24, 36.9%), hepatomegaly (16, 24.6%), and lymphadenopathy (11, 16.9%)]. Total lymphocyte counts were within the normal range for age in 32 (68.1%) and low in 11 (23.4%) patients. Neutropenia in 30 (63.8%), thrombocytopenia in 22 (43.1%), and anemia in 30 (58.8%) patients were reported. The majority of patients with available flowcytometry had normal CD3⁺T (24, 66.7%), CD4⁺T (23, 63.9%), CD8⁺T (24, 66.7%), CD19⁺B (26, 76.5%), and NK (24, 85.7%) cells. The serum levels of IgG (21, 56.8%), IgA (19, 52.8%), IgM (24, 72.7%), and IgE (6, 46.2%) were also in the normal range for age in most patients.

Patients received IgRT (12, 17.6%), corticosteroid (21, 30.9%), and HLH-2004 protocol (24, 35.3%). HSCT was performed in 14 (20.6%) patients at a median (IQR) age of 50.5 (23.5–67.8) months. The highest mortality rate was observed in this group and almost half of the patients (31, 49.2%) died at a median (IQR) age of 52 (36–108) months. For 27 patients, the death reason was available and mainly included HLH surge (9, 33.3%), sepsis (7, 25.9%), pneumonia (5, 18.5%), and lymphoma (3, 11.1%).

## 3.2. Familial Hemophagocytic Lymphohistiocytosis (fHLH)

Twenty-eight patients (8.2%) had defect in one of the PRF1 (14, 50%), UNC13D (11, 39.3%), STX11 (2, 7.1%), and STXBP2 (1, 3.6%) genes. Most patients were Kuwaiti Arab (8, 28.6%), Turkish (4, 14.3%), and Maghrebi Arab-Berber (4, 14.3%). The male: female ratio was 1. The median (IQR) age of the group was 78 (6–179) months. The median (IQR) age at onset was 12 (1–91) months. The median (IQR) age of diagnosis and diagnosis delay were 48 (3–107) and 4 (1–18) months, respectively. The lowest age of manifestation onset was for autoimmune disorders [4 (3–100) months]. Organomegaly (12, 50%) and autoimmunity (6, 25%) were frequently reported as the first manifestations in 24 patients. The most common clinical manifestations were lymphoproliferation (21, 77.8%) [splenomegaly (20, 74.1%), hepatomegaly (8, 29.6%), and lymphadenopathy (7, 25.9%)], infections (10, 37%) [mainly LRTI (3, 11.1%) and chronic diarrhea (3, 11.1%)] and

hematologic autoimmunity (5, 18.5%) [autoimmune hemolytic anemia (AIHA, 3, 11.1%) and neutropenia (3, 11.1%)]. The highest frequency of lymphoproliferation was observed in this group. According to normal ranges for age, most patients had normal lymphocyte (9, 60%) and neutrophil (9, 56.3%) counts but low platelet counts (11, 55%) and low hemoglobin levels (14, 73.7%). Normal circulating CD3⁺T (10, 76.9%), CD4⁺T (10, 71.4%), CD19⁺B (7, 53.8%), and even CD8⁺T (11, 78.6%), and NK (7, 63.6%) cells were detected in the majority. Hypogammaglobulinemia was found in 7 (53.8%), while IgA (6, 46.2%), IgM (8, 57.1%), and IgE (4, 66.7%) were normal in most patients.

Patients underwent treatment with IgRT (13, 65%), corticosteroids (15, 53.6%), and biologic immunosuppressive drugs (8, 28.6%). HSCT was performed in 6 (21.4%) patients at a median (IQR) age of 18 (7–128.5) months. At the end of the survey, 6 patients (24%) deceased following pulmonary hemorrhage (4, 66.7%) and sepsis (2, 33.3%).

## 3.3. EBV susceptibility with HLH

Twenty patients (5.8%) had defect in one of the following: CD27 (10, 50%), XIAP (7, 35%), and SH2D1A (3, 15%). Most patients were Persian (12, 60%), Egyptian Arab (3, 15%), and Omani Arab (2, 10%). The male: female ratio was 2.3. Patients had the highest median (IQR) age (162 (56–270) months) at the time of study compared to other MIDD patients. The median (IQR) age at onset was 60 (6–96) months. The median (IQR) age of diagnosis and diagnosis delay were 96 (34–162) and 24 (4–111) months, respectively. The latest median (IQR) age at presentation of infection belonged to this group (72 (6–96) months). Organomegaly and malignancy were presented at a median (IQR) age of 49 (7–84) and 102 (33–261) months, respectively.

RTI was the most prevalent first presentation in 8 of 17 (47%) patients with available history. The most common clinical manifestations were infections (16, 84.2%) [mainly URTI (10, 52.6%), LRTI (9, 47.4%) and chronic diarrhea (8, 42.1%)] and lymphoproliferation (11, 57.9%) [splenomegaly (8, 42.1%), lymphadenopathy (6, 31.6%), hepatomegaly (5, 26.3%), and malignancy (5, 26.3%)]. The highest frequency of malignancy was observed in this group.

Most patients were found to have normal lymphocytes (17, 89.5%), neutrophils (14, 77.8%), and platelets (14, 87.5%) counts, and normal
<table><caption>**Table 2**
Clinical manifestations in patients with monogenic immune dysregulation diseases.</caption><thead><tr><th></th><th>Total<br>(n = 343)</th><th>HLH with<br>hypopigmentation<br>(n = 68)</th><th>fHLH<br>(n = 28)</th><th>EBV<br>susceptibility<br>without HLH<br>(n = 34)</th><th>EBV<br>susceptibility<br>with HLH<br>(n = 20)</th><th>Syndromes with<br>autoimmunity with high<br>DNT cells but without<br>Tregs defect<br>(n = 22)</th><th>Syndromes with<br>autoimmunity and<br>normal DNT and Tregs<br>(n = 19)</th><th>Syndromes with<br>autoimmunity and Tregs<br>defect but normal DNT cells<br>(n = 120)</th><th>Immune<br>dysregulation<br>with colitis<br>(n = 32)</th><th>p-value</th></tr></thead><tbody><tr><td>Infections, n (%)</td><td>248<br>(75.1)</td><td>44 (67.7)</td><td>10<br>(37)</td><td>27 (81.8)</td><td>16 (84.2)</td><td>8 (36.4)</td><td>16 (84.2)</td><td>102 (87.2)</td><td>26 (83.9)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>URTI, n (%)</td><td>106<br>(31.9)</td><td>13 (20)</td><td>2 (7.4)</td><td>16 (48.5)</td><td>10 (52.6)</td><td>1 (4.5)</td><td>3 (15.8)</td><td>56 (47.9)</td><td>5 (16.1)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Otitis media, n (%)</td><td>67<br>(20.2)</td><td>8 (12.3)</td><td>0</td><td>9 (27.3)</td><td>7 (36.8)</td><td>1 (4.5)</td><td>3 (15.8)</td><td>36 (30.8)</td><td>3 (9.7)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Rhino/Sinusitis, n (%)</td><td>50<br>(15.1)</td><td>1 (1.6)</td><td>1 (3.7)</td><td>8 (24.2)</td><td>7 (36.8)</td><td>0</td><td>1 (5.3)</td><td>30 (25.6)</td><td>2 (6.5)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Pharyngitis, n (%)</td><td>5 (1.5)</td><td>2 (3.1)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>3 (2.6)</td><td>0</td><td>0.743</td><td></td></tr><tr><td>Tonsilitis, n (%)</td><td>7 (2.1)</td><td>3 (4.6)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>4 (3.4)</td><td>0</td><td>0.509</td><td></td></tr><tr><td>LRTI, n (%)</td><td>123<br>(37)</td><td>23 (35.4)</td><td>3<br>(11.1)</td><td>13 (39.4)</td><td>9 (47.4)</td><td>2 (9.1)</td><td>3 (15.8)</td><td>68 (58.1)</td><td>2 (6.5)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Pneumonia, n (%)</td><td>119<br>(35.8)</td><td>22 (33.8)</td><td>3<br>(11.1)</td><td>13 (39.4)</td><td>9 (47.4)</td><td>2 (9.1)</td><td>3 (15.8)</td><td>65 (55.6)</td><td>2 (6.5)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Bronchiectasis, n (%)</td><td>23<br>(6.9)</td><td>2 (3.1)</td><td>0</td><td>2 (6.1)</td><td>2 (10.5)</td><td>0</td><td>1 (5.3)</td><td>16 (13.7)</td><td>0</td><td>0.024<sup>§</sup></td><td></td></tr><tr><td>Bronchiolitis, n (%)</td><td>11<br>(3.3)</td><td>3 (4.6)</td><td>0</td><td>0</td><td>1 (5.3)</td><td>2 (9.1)</td><td>0</td><td>5 (4.3)</td><td>0</td><td>0.431</td><td></td></tr><tr><td>Chronic diarrhea, n (%)</td><td>103<br>(31.0)</td><td>8 (12.3)</td><td>3<br>(11.1)</td><td>7 (21.2)</td><td>8 (42.1)</td><td>4 (18.2)</td><td>5 (26.3)</td><td>52 (44.4)</td><td>16 (51.6)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Abscess, n (%)</td><td>31<br>(9.3)</td><td>3 (4.6)</td><td>0</td><td>2 (6.1)</td><td>1 (5.3)</td><td>1 (4.5)</td><td>0</td><td>7 (6.0)</td><td>17 (54.8)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Candidiasis, n (%)</td><td>30<br>(9.0)</td><td>2 (3.1)</td><td>1 (3.7)</td><td>3 (9.1)</td><td>2 (10.5)</td><td>0</td><td>7 (36.8)</td><td>13 (11.1)</td><td>2 (6.5)</td><td>0.001<sup>§</sup></td><td></td></tr><tr><td>Skin infection, n (%)</td><td>23<br>(6.9)</td><td>1 (1.5)</td><td>2 (7.4)</td><td>4 (12.1)</td><td>3 (15.8)</td><td>0</td><td>2 (10.5)</td><td>7 (6.0)</td><td>4 (12.9)</td><td>0.166</td><td></td></tr><tr><td>Sepsis, n (%)</td><td>23<br>(6.9)</td><td>6 (9.2)</td><td>2 (7.4)</td><td>1 (3.0)</td><td>0</td><td>1 (4.5)</td><td>1 (5.3)</td><td>8 (6.8)</td><td>4 (12.9)</td><td>0.687</td><td></td></tr><tr><td>Conjunctivitis, n (%)</td><td>13<br>(3.9)</td><td>2 (3.1)</td><td>0</td><td>1 (3.0)</td><td>2 (10.5)</td><td>0</td><td>0</td><td>8 (6.8)</td><td>0</td><td>0.249</td><td></td></tr><tr><td>UTI, n (%)</td><td>13<br>(3.9)</td><td>3 (4.6)</td><td>0</td><td>0</td><td>2 (10.5)</td><td>0</td><td>1 (5.3)</td><td>7 (6.0)</td><td>0</td><td>0.306</td><td></td></tr><tr><td>Meningitis, n (%)</td><td>11<br>(3.3)</td><td>2 (3.1)</td><td>1 (3.7)</td><td>1 (3.0)</td><td>3 (15.8)</td><td>0</td><td>0</td><td>4 (3.4)</td><td>0</td><td>0.111</td><td></td></tr><tr><td>Arthritis, n (%)</td><td>8 (2.4)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>8 (6.8)</td><td>0</td><td>0.036<sup>§</sup></td><td></td></tr><tr><td>Oral ulcer, n (%)</td><td>6 (1.8)</td><td>2 (3.1)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>2 (1.7)</td><td>2 (6.5)</td><td>0.473</td><td></td></tr><tr><td>Autoimmunity, n (%)</td><td>136<br>(41)</td><td>8 (12.3)</td><td>5<br>(18.5)</td><td>10 (30.3)</td><td>2 (10.5)</td><td>17 (77.3)</td><td>11 (57.9)</td><td>69 (59)</td><td>14 (45.2)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Hematologic, n (%)</td><td>78<br>(23.5)</td><td>6 (9.2)</td><td>5<br>(18.5)</td><td>4 (12.1)</td><td>0</td><td>16 (72.7)</td><td>3 (15.8)</td><td>44 (37.6)</td><td>0</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>ITP, n (%)</td><td>45<br>(13.6)</td><td>2 (3.1)</td><td>2 (7.4)</td><td>3 (9.1)</td><td>0</td><td>13 (59.1)</td><td>1 (5.3)</td><td>24 (20.5)</td><td>0</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>AIHA, n (%)</td><td>44<br>(13.3)</td><td>0</td><td>3<br>(11.1)</td><td>1 (3.0)</td><td>0</td><td>13 (59.1)</td><td>0</td><td>27 (23.1)</td><td>0</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Evans syndrome, n<br>(%)</td><td>24<br>(7.2)</td><td>0</td><td>1 (3.7)</td><td>0</td><td>0</td><td>11 (50.0)</td><td>0</td><td>12 (10.3)</td><td>0</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Non-specific<br>cytopenia, n (%)</td><td>20<br>(6.0)</td><td>3 (4.6)</td><td>1 (3.7)</td><td>0</td><td>0</td><td>9 (40.9)</td><td>1 (5.3)</td><td>6 (5.1)</td><td>0</td><td>&lt;0.001<sup>§</sup></td><td></td></tr><tr><td>Gastrointestinal, n (%)</td><td>45<br>(13.6)</td><td>1 (1.5)</td><td>0</td><td>4 (12.1)</td><td>1 (5.3)</td><td>2 (9.1)</td><td>3 (15.8)</td><td>20 (17.1)</td><td>14 (45.2)</td><td>&lt;0.001<sup>§</sup></td><td></td></tr></tbody></table>

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<table><caption>Table 2 (continued)</caption><thead><tr><th></th><th>Total<br>(n = 343)</th><th>HLH with<br>hypopigmentation<br>(n = 68)</th><th>fHLH<br>(n = 28)</th><th>EBV<br>susceptibility<br>without HLH<br>(n = 34)</th><th>EBV<br>susceptibility<br>with HLH<br>(n = 20)</th><th>Syndromes with<br>autoimmunity with high<br>DNT cells but without<br>Tregs defect<br>(n = 22)</th><th>Syndromes with<br>autoimmunity and<br>normal DNT and Tregs<br>(n = 19)</th><th>Syndromes with<br>autoimmunity and Tregs<br>defect but normal DNT cells<br>(n = 120)</th><th>Immune<br>dysregulation<br>with colitis<br>(n = 32)</th><th>p-value</th></tr></thead><tbody><tr><td>AI enteropathy, n (%)</td><td>18<br>(5.4)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (4.5)</td><td>1 (5.3)</td><td>10 (8.5)</td><td>6 (19.4)</td><td>0.002*</td></tr><tr><td>IBD, n (%)</td><td>16<br>(4.8)</td><td>0</td><td>0</td><td>4 (12.1)</td><td>1 (5.3)</td><td>0</td><td>0</td><td>3 (2.6)</td><td>8 (25.8)</td><td>&lt;0.001*</td></tr><tr><td>Celiac, n (%)</td><td>6 (1.8)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (5.3)</td><td>5 (4.3)</td><td>0</td><td>0.262</td></tr><tr><td>AI gastritis, n (%)</td><td>4 (1.2)</td><td>1 (1.5)</td><td>0</td><td>0</td><td>0</td><td>1 (4.5)</td><td>0</td><td>2 (1.7)</td><td>0</td><td>0.786</td></tr><tr><td>Rheumatologic, n (%)</td><td>12<br>(3.6)</td><td>1 (1.5)</td><td>0</td><td>1 (3.0)</td><td>0</td><td>0</td><td>0</td><td>10 (8.5)</td><td>0</td><td>0.064</td></tr><tr><td>JIA, n (%)</td><td>5 (1.5)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>5 (4.3)</td><td>0</td><td>0.232</td></tr><tr><td>ERA, n (%)</td><td>4 (1.2)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>4 (3.4)</td><td>0</td><td>0.387</td></tr><tr><td>SLE, n (%)</td><td>1 (0.3)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (0.9)</td><td>0</td><td>0.968</td></tr><tr><td>Kawasaki, n (%)</td><td>1 (0.3)</td><td>1 (1.5)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0.758</td></tr><tr><td>Behçet's disease, n<br>(%)</td><td>1 (0.3)</td><td>0</td><td>0</td><td>1 (3.0)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0.248</td></tr><tr><td>Endocrine, n (%)</td><td>29<br>(8.7)</td><td>0</td><td>0</td><td>1 (3.0)</td><td>1 (5.3)</td><td>0</td><td>8 (42.1)</td><td>19 (16.2)</td><td>0</td><td>&lt;0.001*</td></tr><tr><td>AI thyroiditis, n (%)</td><td>17<br>(5.1)</td><td>0</td><td>0</td><td>1 (3.0)</td><td>1 (5.3)</td><td>0</td><td>7 (36.8)</td><td>8 (6.8)</td><td>0</td><td>&lt;0.001*</td></tr><tr><td>IDDM, n (%)</td><td>15<br>(4.5)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>15 (12.8)</td><td>0</td><td>&lt;0.001*</td></tr><tr><td>AI adrenalitis, n (%)</td><td>5 (1.5)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>4 (21.1)</td><td>1 (0.9)</td><td>0</td><td>&lt;0.001*</td></tr><tr><td>Cutaneous, n (%)</td><td>10<br>(3.0)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>2 (10.5)</td><td>8 (6.8)</td><td>0</td><td>0.029*</td></tr><tr><td>Psoriasis, n (%)</td><td>6 (1.8)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>6 (5.1)</td><td>0</td><td>0.130</td></tr><tr><td>Alopecia, n (%)</td><td>2 (0.6)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (5.3)</td><td>1 (0.9)</td><td>0</td><td>0.317</td></tr><tr><td>Vitiligo, n (%)</td><td>2 (0.6)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (5.3)</td><td>1 (0.9)</td><td>0</td><td>0.317</td></tr><tr><td>Neurologic, n (%)</td><td>3 (0.9)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (5.3)</td><td>2 (1.7)</td><td>0</td><td>0.466</td></tr><tr><td>Myasthenia gravis, n<br>(%)</td><td>2 (0.6)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>2 (1.7)</td><td>0</td><td>0.834</td></tr><tr><td>Neuritis, n (%)</td><td>1 (0.3)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (5.3)</td><td>0</td><td>0</td><td>0.021*</td></tr><tr><td>Other AI disorders, n<br>(%)</td><td>5 (1.5)</td><td>0</td><td>1 (3.7)</td><td>0</td><td>0</td><td>0</td><td>1 (5.3)</td><td>3 (2.6)</td><td>0</td><td>0.517</td></tr><tr><td>Lymphoproliferation, n<br>(%)</td><td>178<br>(53.8)</td><td>28 (43.1)</td><td>21<br>(77.8)</td><td>18 (54.5)</td><td>11 (57.9)</td><td>18 (81.8)</td><td>2 (10.5)</td><td>77 (65.8)</td><td>3 (9.7)</td><td>&lt;0.001*</td></tr><tr><td>Splenomegaly, n (%)</td><td>149<br>(44.9)</td><td>24 (36.9)</td><td>20<br>(74.1)</td><td>15 (45.5)</td><td>8 (42.1)</td><td>16 (72.7)</td><td>2 (10.5)</td><td>63 (53.8)</td><td>2 (6.5)</td><td>&lt;0.001*</td></tr><tr><td>Lymphadenopathy, n<br>(%)</td><td>84<br>(25.3)</td><td>11 (16.9)</td><td>7<br>(25.9)</td><td>9 (27.3)</td><td>6 (31.6)</td><td>15 (68.2)</td><td>0</td><td>36 (30.8)</td><td>0</td><td>&lt;0.001*</td></tr><tr><td>Hepatomegaly, n (%)</td><td>82<br>(24.7)</td><td>16 (24.6)</td><td>8<br>(29.6)</td><td>3 (9.1)</td><td>5 (26.3)</td><td>11 (50.0)</td><td>1 (5.3)</td><td>37 (31.6)</td><td>1 (3.2)</td><td>&lt;0.001*</td></tr><tr><td>Malignancy, n (%)</td><td>26<br>(7.8)</td><td>2 (3.1)</td><td>1 (3.7)</td><td>6 (18.2)</td><td>5 (26.3)</td><td>2 (9.1)</td><td>0</td><td>9 (7.7)</td><td>1 (3.2)</td><td>0.008*</td></tr><tr><td>Atopy, n (%)</td><td>62<br>(18.7)</td><td>6 (9.2)</td><td>3<br>(11.1)</td><td>6 (18.2)</td><td>4 (21.1)</td><td>5 (22.7)</td><td>4 (21.1)</td><td>29 (24.8)</td><td>5 (16.1)</td><td>0.330</td></tr><tr><td>Asthma, n (%)</td><td>30<br>(9.0)</td><td>2 (3.1)</td><td>1 (3.7)</td><td>5 (15.2)</td><td>2 (10.5)</td><td>2 (9.1)</td><td>1 (5.3)</td><td>17 (14.5)</td><td>0</td><td>0.075</td></tr><tr><td>Eczema/Atopic<br>dermatitis, n (%)</td><td>13<br>(3.9)</td><td>2 (3.1)</td><td>1 (3.7)</td><td>1 (3.0)</td><td>1 (5.3)</td><td>1 (4.5)</td><td>1 (5.3)</td><td>4 (3.4)</td><td>2 (6.5)</td><td>0.995</td></tr><tr><td>Food allergy, n (%)</td><td>10<br>(3.0)</td><td>0</td><td>0</td><td>0</td><td>1 (5.3)</td><td>1 (4.5)</td><td>2 (10.5)</td><td>3 (2.6)</td><td>3 (9.7)</td><td>0.077</td></tr><tr><td></td><td>4 (1.2)</td><td>1 (1.5)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>3 (2.6)</td><td>0</td><td>0.812</td></tr></tbody></table>

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<table><caption>Table 2 (continued)</caption><thead><tr><th></th><th>Total<br>(n = 343)</th><th>HLH with<br>hypopigmentation<br>(n = 68)</th><th>fHLH<br>(n = 28)</th><th>EBV<br>susceptibility<br>without HLH<br>(n = 34)</th><th>EBV<br>susceptibility<br>with HLH<br>(n = 20)</th><th>Syndromes with<br>autoimmunity with high<br>DNT cells but without<br>Tregs defect<br>(n = 22)</th><th>Syndromes with<br>autoimmunity and<br>normal DNT and Tregs<br>(n = 19)</th><th>Syndromes with<br>autoimmunity and Tregs<br>defect but normal DNT cells<br>(n = 120)</th><th>Immune<br>dysregulation<br>with colitis<br>(n = 32)</th><th>p-value</th></tr></thead><tbody><tr><td>Allergic bronchiolitis, n<br>(%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Allergic rhinitis, n (%)</td><td>5 (1.5)</td><td>0</td><td>0</td><td>2 (6.1)</td><td>0</td><td>0</td><td>0</td><td>3 (2.6)</td><td>0</td><td>0.311</td></tr><tr><td>Urticaria, n (%)</td><td>2 (0.6)</td><td>0</td><td>1 (3.7)</td><td>0</td><td>0</td><td>1 (4.5)</td><td>0</td><td>0</td><td>0</td><td>0.110</td></tr><tr><td>Anaphylaxis, n (%)</td><td>2 (0.6)</td><td>1 (1.5)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (0.9)</td><td>0</td><td>0</td><td>0.959</td></tr></tbody></table>

M; male, F; female, D; dead, A; alive, URTI; upper respiratory tract infection, UTRI; lower respiratory tract infection, UTRI; urinary tract infection, HLH; Hemophagocytic lymphohistiocytosis, fHLH; familial HLH, EBV; Epstein-Barr virus, DNT; double negative T lymphocytes, ITP; immune thrombocytopenic purpura, AIHA; autoimmunity, JRA; juvenile idiopathic arthritis, IBD; inflammatory bowel disease, ERA; enthesitis-related arthritis, SLE; systemic lupus erythematosus, IDDM; insulin-dependent diabetes mellitus.

hemoglobin level (11, 61.1%). Flowcytometry analysis of most patients showed high CD3⁺ T (5, 41.7%) and CD8⁺ T (8, 80%), normal CD4⁺ T (7, 63.6%) and NK (4, 57.1%), and low CD19⁺ B (5, 55.6%) cells. Low serum IgG (12, 63.2%), IgA (11, 57.9%), IgM (12, 63.2%) and normal IgE (13, 76.5%) were documented in the majority. Patients received treatment with IgRT (8, 40%), corticosteroids (5, 25%), and biologic immunosuppressives (6, 30%). HSCT was performed in 3 (15%) patients at the ages of 36, 37 and 126 months. At the end of the survey, 8 patients (44.4%) deceased and multiorgan failure was the main cause of death in two patients.

### 3.4. EBV susceptibility without HLH

Thirty-four (9.9%) patients had defect in one of the TNFRSF9 (10, 29.4%), RLTTR (10, 29.4%), CD70 (6, 17.6%), PRKCD (5, 14.7%), MAGT1 (2, 5.9%), and RASGRP1 (1, 2.9%). Most patients belonged to Turkish (17, 50%), Persian (8, 23.5%), and Kuwaiti Arab (6, 17.6%) ethnic groups. The male: female ratio was 1. The median (IQR) age in the study was 144 (67–208) months. The median (IQR) age at onset was 36 (4–90) months. This group had the highest median (IQR) age of diagnosis [117 (49–163) months] and diagnosis delay [48 (24–90) months] among other MIDD categories. Atopy had the lowest median age of presentation (24 months), followed by infection (36 months), organomegaly (48 months), autoimmunity (96 months), and malignancy (122 months).

First presentation was reported in 32 patients and mostly included RTI (10, 31.2%), organomegaly (7, 21.9%), and diarrhea (5, 15.6%). The most common clinical manifestations were infections (27, 81.8%) [mainly URTI (16, 48.5%), LRTI (13, 39.4%) and chronic diarrhea (7, 21.2%)], lymphoproliferation (18, 54.5%) [splenomegaly (15, 45.5%) and lymphadenopathy (9, 27.3%)], and autoimmunity (10, 30.3%) [Inflammatory bowel disease (IBD, 4, 12.1%) and idiopathic thrombocytopenic purpura (ITP, 3, 9.1%)].

Total lymphocyte counts were within the normal range for age in the majority of patients (23, 85.2%). In addition, most patients had normal neutrophil (20, 76.9%), and platelet (21, 67.7%) counts, but low level of hemoglobin (17, 53.1%). The flow cytometry results were indicative of normal CD3⁺ T (21, 91.3%), CD4⁺ T (18, 78.3%), CD8⁺ T (19, 82.6%), CD19⁺ B (16, 69.6%), and NK (12, 60%) cells in most patients. The serum level of IgG was low in 12 (46.2%) patients, while other immunoglobulins including IgA (19, 73.1%), IgM (16, 61.5%), and IgE (18, 72%) were mainly in the normal range for age. Tregs were assessed in seven patients and all were reduced. DNT and CD21low B cells were normal in 11 (78.6%) and 10 (71.4%) patients, respectively.

Patients underwent treatment with IgRT (20, 58.8%), corticosteroids (11, 32.4%), biologic immunosuppressive (8, 23.5%), and surgeries (3, 8.8%). HSCT was performed in 3 (8.8%) patients at the ages of 27, 132, and 144 months. At the end of the survey, 7 patients (21.9%) deceased, and sepsis was stated as the cause of death in three patients.

### 3.5. Syndromes with autoimmunity with high DNT cells but normal Tregs

Twenty-two patients (6.4%) had defect in one of the TNFRSF6 (17, 77.3%), FASLG (2, 9.1%), FADD (1, 4.5%), CASP8 (1, 4.5%), and CASP10 (1, 4.5%). Most patients were Maghrebi Arab-Berber (12, 54.5%) and Kuwaiti Arab (4, 18.2%). The male: female ratio was 2.1 despite absence of X-linked disease in this group. The median (IQR) age at study was 54 (29–163) months. The median (IQR) age at onset was 7 (3–14) months. This group had the lowest median (IQR) age of diagnosis (16 (10–56) months) among other MIDD categories. The median (IQR) diagnosis delay was 10 (3–48) months. The median (IQR) age at onset of organomegaly, infection, autoimmunity, and atopy were 8 (4–14), 8 (5–30), 10 (6–42), and 18 (3–69) months, respectively.

The first presentations included organomegaly (9, 40.9%), autoimmunity (5, 22.7%), and RTI (3, 13.6%).

The most common clinical manifestations were lymphoproliferation

<footnote>* A p-value < 0.05 is considered as significant.</footnote>
<table><caption>**Table 3**
Immunologic profile in patients with monogenic immune dysregulation diseases.</caption><thead><tr><th></th><th>Total<br>(n = 343)</th><th>HLH with<br>hypopigmentation<br>(n = 68)</th><th>fHLH<br>(n = 28)</th><th>EBV susceptibility<br>without HLH<br>(n = 34)</th><th>EBV<br>susceptibility<br>with HLH<br>(n = 20)</th><th>Syndromes with<br>autoimmunity with<br>high DNT cells but<br>without Tregsdefect<br>(n = 22)</th><th>Syndromes with<br>autoimmunity and<br>normal DNT and<br>Tregs (n = 19)</th><th>Syndromes with<br>autoimmunity and<br>Tregs defect but<br>normal DNT cells (n =<br>120)</th><th>Immune<br>dysregulation<br>with colitis<br>(n = 32)</th><th>p-value</th></tr></thead><tbody><tr><td>WBC × 10<sup>3</sup> (cell/<br>μL), median (IQR)<br>(n = 288)</td><td>7210<br>(4770-11,650)</td><td>6300 (3600-9645)</td><td>5400<br>(3500-7800)</td><td>7350<br>(5550-10,297.5)</td><td>6600<br>(5600-9500)</td><td>13,200 (5700-17,000)</td><td>8130 (5900-9400)</td><td>6800 (4750-12,115)</td><td>16,750<br>(5700-22,700)</td><td>&lt;0.001*</td></tr><tr><td>Absolute<br>lymphocytes<br>count × 10<sup>3</sup> (cells<br>/μL), median<br>(IQR) (n = 265)</td><td>2320<br>(735-4975)</td><td>4020 (2203-6945)</td><td>2300<br>(1109.5-3250)</td><td>2600<br>(1725-4620)</td><td>2300<br>(49-4000)</td><td>7481 (3146.3-10,673)</td><td>2850 (55-4210)</td><td>1400 (52.5-2931)</td><td>1688<br>(71.3-6275)</td><td>&lt;0.001*</td></tr><tr><td>Absolute<br>neutrophils count<br>× 10<sup>3</sup> (cells /μL),<br>median (IQR) (n<br>= 262)</td><td>1985<br>(146.8-4270)</td><td>1050 (137.5-1800)</td><td>1960<br>(540-3381)</td><td>4450<br>(2867.5-5475)</td><td>1400<br>(46-3910)</td><td>2967 (1837.3-4650)</td><td>2180 (64-3830)</td><td>1822.5 (68.8-4335)</td><td>3962<br>(753.5-9940)</td><td>&lt;0.001*</td></tr><tr><td>Hb (g/dL), median<br>(IQR) (n = 280)</td><td>11 (8.8-12.8)</td><td>10.4 (8.6-12)</td><td>8.4 (8-12.8)</td><td>11.4 (9.2-12)</td><td>12 (10.9-13.9)</td><td>8.5 (7.4-10.7)</td><td>12 (11.2-13.6)</td><td>12 (9.9-13.1)</td><td>9.8 (8.6-10.9)</td><td>&lt;0.001*</td></tr><tr><td>Platelet × 10<sup>3</sup> (cells<br>/μL), median<br>(IQR) (n = 269)</td><td>234<br>(119-346.5)</td><td>199 (90-311)</td><td>99 (49-207)</td><td>297 (158-362)</td><td>213.5<br>(163-287.8)</td><td>106.5 (64.8-251)</td><td>310 (113-398)</td><td>261.5 (177.3-366.8)</td><td>267 (212.5-509)</td><td>&lt;0.001*</td></tr><tr><td>CD3<sup>+</sup> T cells, % of<br>lymph, median<br>(IQR) (n = 226)</td><td>71 (62-78.4)</td><td>68.4 (60.3-76.9)</td><td>82.4<br>(70.5-90.2)</td><td>73.4 (67.3-79.6)</td><td>75.9<br>(67.8-84.8)</td><td>59 (54-83.3)</td><td>64.3 (58.3-80.8)</td><td>71 (63.3-77.2)</td><td>65 (59.4-73.3)</td><td>0.012*</td></tr><tr><td>CD4<sup>+</sup> T cells, % of<br>lymph, median<br>(IQR) (n = 225)</td><td>36.5<br>(29.2-43.4)</td><td>35.3 (30.3-39.5)</td><td>42.3 (37-51.8)</td><td>38.4 (32-49.3)</td><td>33.5 (12.9-37)</td><td>28 (22-35)</td><td>39.8 (30.5-45.7)</td><td>35.8 (29.8-45)</td><td>39 (26.3-44.3)</td><td>0.025*</td></tr><tr><td>CD8<sup>+</sup> T cells, % of<br>lymph, median<br>(IQR) (n = 223)</td><td>28.4 (22.1-39)</td><td>27.9 (21-35)</td><td>26 (21.4-39.8)</td><td>27 (21.4-35.5)</td><td>43 (35-58.2)</td><td>29 (14.5-37)</td><td>26.2 (23-28.7)</td><td>29 (22.2-41.5)</td><td>27 (21-38)</td><td>0.046*</td></tr><tr><td>CD19<sup>+</sup> B cells, % of<br>lymph, median<br>(IQR) (n = 224)</td><td>14.8 (6.2-22)</td><td>22.1 (12.8-29.9)</td><td>5.4 (2.3-15.5)</td><td>14 (4.6-22.2)</td><td>8.7 (2-19.9)</td><td>18.5 (8.4-26.8)</td><td>16.2 (10.5-23.8)</td><td>13 (5-18.9)</td><td>18 (16-34)</td><td>&lt;0.001*</td></tr><tr><td>NK cell, % of lymph,<br>median (IQR) (n<br>= 166)</td><td>8 (4.8-11.9)</td><td>7.1 (4.8-11.6)</td><td>6.5 (5.5-11.5)</td><td>3.7 (2.1-6.6)</td><td>5.1 (2.2-10.6)</td><td>8 (6.2-10.3)</td><td>4.9 (2.1-10)</td><td>8.9 (5-12.9)</td><td>12.7 (8.5-16.5)</td><td>0.001</td></tr><tr><td>CD4 + CD25 +<br>FOXP3+ cells (%<br>of CD4+ T cells),<br>median (IQR) (n<br>= 35)</td><td>0.9 (0.3-2)</td><td>-</td><td>0</td><td>0.5 (0.2-1.3)</td><td>1.0</td><td>-</td><td>2.1</td><td>0.9 (0.3-1.8)</td><td>4.11</td><td>0.501</td></tr><tr><td>Double-negative T<br>cells (% of CD3+<br>T cells), median<br>(IQR) (n = 53)</td><td>3.5 (1.3-7.6)</td><td>7.5</td><td>0</td><td>1.3 (0.9-2.8)</td><td>0</td><td>9.3 (4.6-27.4)</td><td>3.0</td><td>4.4 (1.4-5.5)</td><td>3.1</td><td>0.013*</td></tr><tr><td>CD21<sup>low</sup> B cell (% of<br>B cells), median<br>(IQR) (n = 47)</td><td>3 (2-7.5)</td><td>-</td><td>0</td><td>3.3 (1.7-5.0)</td><td>0</td><td>-</td><td>4</td><td>2.3 (2-17.6)</td><td>2.5</td><td>0.581</td></tr><tr><td>Th17 (% of CD4+ T<br>cells), median<br>(IQR) (n = 14)</td><td>0.5 (0.3-0.7)</td><td>-</td><td>0</td><td>-</td><td>0</td><td>-</td><td>-</td><td>0.5 (0.3-0.7)</td><td>0</td><td>-</td></tr><tr><td></td><td>645<br>(343-1150)</td><td>637 (221-1135)</td><td>390 (264-722)</td><td>706<br>(472.3-1508.5)</td><td>500 (426-866)</td><td>1569 (892.8-3403.3)</td><td>1201.5<br>(897.3-1390.3)</td><td>565 (305-910.5)</td><td>828<br>(467-1015.5)</td><td>&lt;0.001*</td></tr></tbody></table>

(continued on next page)
<table><caption>Table 3 (continued)</caption><thead><tr><th></th><th>Total<br>(n = 343)</th><th>HLH with<br>hypopigmentation<br>(n = 68)</th><th>fHLH<br>(n = 28)</th><th>EBV susceptibility<br>without HLH<br>(n = 34)</th><th>EBV susceptibility<br>with HLH<br>(n = 20)</th><th>Syndromes with<br>autoimmunity with<br>high DNT cells but<br>without Tregsdetect<br>(n = 22)</th><th>Syndromes with<br>autoimmunity and<br>normal DNT and<br>Tregs (n = 19)</th><th>Syndromes with<br>autoimmunity and<br>Tregs defect but<br>normal DNT cells (n =<br>120)</th><th>Immune<br>dysregulation<br>with colitis<br>(n = 32)</th><th>p-value</th></tr></thead><tbody><tr><td>lgG (mg/dL),<br>median (IQR) (n<br>= 257)</td><td>44.5</td><td>67.3 (25–132.3)</td><td>27 (19–90)</td><td>83.5 (47–235.5)</td><td>23 (10–46)</td><td>287 (58.5–421)</td><td>108.5 (59.4–187)</td><td>20 (6–59.3)</td><td>91 (43.5–115.5)</td><td>&lt;0.001*</td></tr><tr><td>lgA (mg/dL),<br>median (IQR) (n<br>= 254)</td><td>(12.5–112.3)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>lgM (mg/dL),<br>median (IQR) (n<br>= 250)</td><td>69.5<br>(27.8–130.5)</td><td>57.1 (17–126.3)</td><td>51<br>(41.5–117.8)</td><td>106 (58.3–271)</td><td>26.7 (1–90)</td><td>116.5 (35.8–166.8)</td><td>112 (61–181)</td><td>60.7 (25–107)</td><td>93 (67.7–181.5)</td><td>0.001*</td></tr><tr><td>lgE (IU/ml), median<br>(IQR) (n = 184)</td><td>7 (1–29.8)</td><td>93.5 (29.7–125.5)</td><td>10 (0.8–20)</td><td>9.6 (2.9–31.3)</td><td>3 (0.5–12)</td><td>14 (4–49.6)</td><td>9 (4–2283.8)</td><td>4 (1–20)</td><td>13 (4.3–34)</td><td>0.001*</td></tr></tbody></table>

M: male, F: female, D: dead, A: alive, lymph: lymphocyte, IQR: interquartile range, HLH: Hemophagocytic lymphohistiocytosis, fHLH: familial HLH, EBV: Epstein-Barr virus, DNT: double negative T lymphocytes, WBC: white blood cells, Hb: hemoglobin, Th17: T helper 17 cells, Ig: immunoglobulin. The data were analyzed by Kruskal-Wallis test. * All ages are in month. * A p-value < 0.05 is considered as significant.

(18, 81.8%) [splenomegaly (16, 72.7%), lymphadenopathy (15, 68.2%), and hepatomegaly (11, 50.0%)], autoimmunity (17, 77.3%) [ITP (13, 59.1%), AIHA (13, 59.1%), and Evans syndrome (11, 50%)], and infections [LRTI (2, 9.1%) and chronic diarrhea (4, 18.2%)]. The highest frequency of autoimmunity was observed in this group. Total lymphocyte counts were higher than normal ranges for age in the majority of patients (11, 61.1%). Normal neutrophil count (13, 72.2%), thrombocytopenia (12, 60%), andanemia (17, 85%) were found in most patients. All lymphocyte subsets were mainly within the normal limits including CD3⁺T (13, 76.5%), CD4⁺T (12, 70.6%), CD8⁺T (9, 52.9%), CD19⁺B (12, 70.6%), and NK (12, 85.7%) cells. Serum IgG (12, 66.7%) and IgA (10, 55.6%) were higher than upper limits for age, while low IgM (8, 47.1%) and normal IgE (4, 80%) were found in most patients. DNT cells were high in all 11 evaluated patients.

Patients underwent treatment with IgRT (5, 22.7%), corticosteroids (13, 59.1%), biologic immunosuppressives (4, 18.1%), and surgeries (2, 9.1%). HSCT was performed in 2 (9.1%) patients at 5 and 13 months. At the end of the survey, 5 patients (35.7%) deceased, two following sepsis and generalized tuberculosis.

### 3.6. Syndromes with autoimmunity and normal DNT and Tregs

Nineteen patients (5.5%) had defect in one of the (13, 68.4%), PEPD (3, 15.8%), TPP2 (2, 10.5%), or ITCH (1, 5.3%). Most patients belonged to Persian (8, 42.1%), Turkish (5, 26.3%), or Kuwaiti Arab (4, 21.1%) ethnic groups. The male: female ratio was 1.7. The median (IQR) age was 160 (96–225) months. The median (IQR) age at onset was 24 (3–36) months. The median (IQR) age of diagnosis and diagnosis delay were 48 (23–87) and 27 (9–54) months, respectively. Atopy, infection, and autoimmunity initially manifested at a median (IQR) age of 10 (3–22), 12 (4–48), and 30 (15–48) months, respectively.

First presentations were available in 17 patients and mainly included autoimmunity (6, 31.6%) and non-respiratory tract infections (5, 26.3%). The most common clinical manifestations were infections (16, 84.2%) [candidiasis (7, 36.8%), chronic diarrhea (5, 26.3%), URTI (3, 15.8%), and LRTI (3, 15.8%)], autoimmunity (11, 57.9%) [autoimmune thyroiditis (7, 36.8%) and autoimmune adrenalitis (4, 21.1%)], and atopy (4, 21.1%) [food allergy (2, 10.5%)]. Most patients demonstrated normal counts of lymphocytes (12, 80%), neutrophils (9, 60%), platelets (11, 73.3%), and hemoglobin (11, 73.3%). In addition, normal counts of CD3⁺T (8, 66.7%), CD4⁺T (9, 75%), CD8⁺T (10, 83.3%), CD19⁺B (9, 75%), NK (5, 62.5%) cells, and normal serum levels of IgG (8, 61.5%), IgA (8, 61.5%), IgM (9, 69.2%), and IgE (6, 60%) were identified in the majority. Gradual reduction in Tregs and increase in the frequency of DNT cells were found exceptionally each in one patient. CD21low B cells were normal in two evaluated patients.

Patients underwent treatment with IgRT (3, 15.8%), corticosteroids (4, 21.1%), biologic immunosuppressives (4, 21.1%), and surgeries (1, 5.3%). No patient received HSCT. The lowest mortality rate was observed in this group (1, 5.6%) which was due to COVID-19 infection.

### 3.7. Syndromes with autoimmunity and Tregs defect but normal DNT cells

One hundred twenty (35%) patients had defect in one of the LRBA (82, 68.3%), FOXP3 (19, 15.8%), CTLA4 (10, 8.3%), STAT3 (6, 5%), or IL2RA (3, 2.5%). Most patients were Persian (47, 39.2%), Turkish (32, 26.7%), or Jordanian Arab (8, 6.7%). The male: female ratio was 1.7. The median (IQR) age was 144 (77–228) months. The median (IQR) age at onset was 18 (7–48) months. The median (IQR) age of diagnosis and diagnosis delay were 84 (34–144) and 37 (12–95) months, respectively. Infections were the earliest presentation at a median (IQR) age of 30 (8–84) months, followed by autoimmunity [42 (11–99) months], atopy [48 (15–123) months], organomegaly [60 (18–120) months], and malignancy [146 (48–240) months].

First presentations were available in 102 patients and mainly
<figure><img src="image_5.png" /><figcaption>**Fig. 3.** The frequency of genes, inheritance pattern and most frequent variants (>4 unique patients) associated with monogenic immune dysregulation diseases.</figcaption></figure>

included RTI (34, 28.3%), autoimmunity (30, 25%), and diarrhea (19, 15.8%).

The most common clinical manifestations were infections (102, 87.2%), [LRTI (68, 58.1%), URTI (56, 47.9%), and chronic diarrhea (52, 44.4%)], lymphoproliferation (77, 65.8%) [splenomegaly (63, 53.8%), hepatomegaly (37, 31.6%), lymphadenopathy (36, 30.8%)], autoimmunity (69, 59%) [AIHA (27, 23.1%), ITP (24, 20.5%), autoimmune enteropathy (10, 8.5%)], and atopy (29, 24.8%) [asthma (17, 14.5%)]. The highest frequency of atopy was observed in this group. EBV infection or viremia was reported in 7 (9.3%) and 1 (10%), while CMV infection or viremia was observed in 8 (10.7%) and 2 (20%) of patients with LRBA and CTLA4 mutations, respectively.

Total lymphocyte counts were within the normal range for age in 67 (63.8%) and low in 33 (31.4%) patients. The neutrophils (66, 64.1%), platelets (73, 74.5%), and hemoglobin (59, 55.7%) was normal in most patients. Most patients had normal lymphocyte subsets, yet low CD3⁺ T (34, 31.5%), CD4⁺ T (33, 30.6%), CD19⁺ B (47, 44.8%), NK (7, 10.3%) cells and high CD8⁺ T (33, 30.8%) counts were predominant flowcytometry patterns. Low IgG (64, 58.7%), IgA (63, 58.3%), and normal IgM (49, 45.4%) and IgE (67, 72.8%) were recorded for most patients.

Th17 cells were reduced in 6 of 14 (42.9%) tested patients. Almost half of the patients had high CD21low B cells and DNT cells were slightly high in 15 cases. The normal counts of Tregs also were observed in 37% of patients showing a minority that have only qualitative but not a quantitative defect.

IgRT, corticosteroids, and biologic immunosuppressives were administered in 67 (55.8%), 58 (48.3%), and 58 (48.3%) patients, respectively. Four (3.3%) patients required surgery, particularly splenectomy. Eighteen patients (15%) received HSCT at a median (IQR) age of 50 (25.5–154.5) months. 28 patients (27.7%) deceased at a median (IQR) age of 99 (37–219) months. Sepsis (6, 26.1%) and pneumonia (5, 21.7%) were the two most common causes of death.

### 3.8. *Immune dysregulation with colitis*

Thirty-two (9.3%) patients had defect in one of the *IL10RB* (13, 40.6%), *RIPK1* (8, 25%), *IL10RA* (6, 18.8%) and *IL10* (5, 15.6%). Most patients were Persian (15, 46.9%), Maghrebi Arab-Berber (7, 21.9%), or Kuwaiti Arab (4, 12.5%). The male: female ratio was 1.5. The median (IQR) age of the group was 66 (38–126) months. This group had the
<caption>**Table 4**</caption>

Detailed available data on transplanted patients with monogenic immune dysregulation diseases.

<table><thead><tr><th>Pt<br>ID</th><th>Country<br>(Ethnicity)</th><th>Gene<br>defect</th><th>Age at<br>1ST HSCT<br>(month)</th><th>Donor, HLA-<br>matching</th><th>Type<br>(source)</th><th>Conditioning</th><th>GVHD<br>prophylaxis</th><th>GVHD (Organ, grade)</th><th>Outcome<br>(Death<br>reason)</th><th>Duration of<br>follow-up<br>(month)</th></tr></thead><tbody><tr><td>1</td><td>Jordan</td><td>LRBA</td><td>24</td><td>MSD</td><td>BM</td><td>Flu, Bu, ATG</td><td>CSA, Cs</td><td>–</td><td>Alive</td><td>48</td></tr><tr><td>2</td><td>UAE</td><td>LRBA</td><td>161</td><td>MSD</td><td>BM</td><td>NA</td><td>NA</td><td>–</td><td>Dead</td><td>–</td></tr><tr><td>3</td><td>Turkey</td><td>LRBA</td><td>27</td><td>MSD</td><td>BM</td><td>Flu, Bu, Cy</td><td>NA</td><td>–</td><td>Alive</td><td>36</td></tr><tr><td>4</td><td>UAE</td><td>LRBA</td><td>159</td><td>MMUD</td><td>BM</td><td>NA</td><td>NA</td><td>Severe GVHD (GI)</td><td>Dead</td><td>3</td></tr><tr><td>5</td><td>Turkey</td><td>LRBA</td><td>300</td><td>MSD</td><td>BM</td><td>Flu, Treo</td><td>CSA, Cs</td><td>GVHD (GI)</td><td>Alive</td><td>18</td></tr><tr><td>6</td><td>Turkey</td><td>LRBA</td><td>120</td><td>MSD</td><td>BM</td><td>Bu, Cy, ATG</td><td>CSA, Cs</td><td>GVHD (GI)</td><td>Alive</td><td>84</td></tr><tr><td>7</td><td>Egypt</td><td>LRBA</td><td>150</td><td>MSD</td><td>BM</td><td>NA</td><td>NA</td><td>Rejection, sepsis</td><td>Dead</td><td>–</td></tr><tr><td>8</td><td>Turkey</td><td>LRBA</td><td>144</td><td>MMUD</td><td>BM</td><td>Flu, Bu</td><td>NA</td><td>GVHD, Renal failure</td><td>Dead</td><td>3</td></tr><tr><td>9</td><td>Turkey</td><td>LRBA</td><td>228</td><td>MUD</td><td>BM</td><td>Flu, Bu</td><td>CSA</td><td>Acute GVHD</td><td>Alive</td><td>32</td></tr><tr><td>10</td><td>Oman</td><td>LRBA</td><td>20</td><td>MSD</td><td>BM</td><td>Flu, Treo,<br>Thio</td><td>Cs</td><td>–</td><td>Alive</td><td>23</td></tr><tr><td>11</td><td>Iran</td><td>LRBA</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>Alive</td><td>–</td></tr><tr><td>12</td><td>Turkey</td><td>FOXP3</td><td>31</td><td>MSD</td><td>BM</td><td>Flu, Bu, Cy</td><td>CSA, ATG,<br>MTX</td><td>CMV reactivation</td><td>Alive</td><td>38</td></tr><tr><td>13</td><td>Turkey</td><td>FOXP3</td><td>36</td><td>MUD</td><td>CB</td><td>NA</td><td>NA</td><td>Graft failure</td><td>Dead</td><td>8</td></tr><tr><td>14</td><td>Turkey</td><td>FOXP3</td><td>8</td><td>MSD</td><td>BM</td><td>NA</td><td>NA</td><td>–</td><td>Alive</td><td>–</td></tr><tr><td>15</td><td>Turkey</td><td>FOXP3</td><td>3</td><td>MUD</td><td>CB</td><td>NA</td><td>NA</td><td>Respiratory Insufficiency</td><td>Dead</td><td>1</td></tr><tr><td>16</td><td>Jordan</td><td>FOXP3</td><td>30</td><td>MSD</td><td>BM</td><td>Flu, Bu, ATG</td><td>CSA, Cs</td><td>CMV reactivation</td><td>Alive</td><td>30</td></tr><tr><td>17</td><td>UAE</td><td>IL2RA</td><td>146</td><td>Haploidentical</td><td>BM</td><td>NA</td><td>NA</td><td>GVHD (liver)</td><td>Dead</td><td>–</td></tr><tr><td>18</td><td>Iran</td><td>STAT3-<br>GOF</td><td>50</td><td>MSD</td><td>BM</td><td>Flu, Bu,<br>r-ATG,<br>Flu, Treo,<br>Thio</td><td>CSA, MMF</td><td>–</td><td>Dead<br>(Sepsis)</td><td>16</td></tr><tr><td>19</td><td>Oman</td><td>RAB27A</td><td>31</td><td>MFD</td><td>BM</td><td>NA</td><td>Cs</td><td>–</td><td>Alive</td><td>1</td></tr><tr><td>20</td><td>Qatar</td><td>RAB27A</td><td>28</td><td>MSD</td><td>BM</td><td>RIC (NA)</td><td>NA</td><td>–</td><td>Alive</td><td>–</td></tr><tr><td>21</td><td>Iran</td><td>RAB27A</td><td>66</td><td>MMUD</td><td>CB</td><td>Flu, Melph,<br>ATG (RIC)</td><td>CSA, Cs</td><td>–</td><td>Alive</td><td>–</td></tr><tr><td>22</td><td>Turkey</td><td>RAB27A</td><td>65</td><td>MUD</td><td>BM</td><td>NA</td><td>NA</td><td>–</td><td>Alive</td><td>10</td></tr><tr><td>23</td><td>Oman</td><td>RAB27A</td><td>157</td><td>Haploidentical</td><td>PBSC</td><td>Flu, Treo,<br>TBI, PTCy</td><td>Tacro</td><td>GVHD (Skin)</td><td>Alive</td><td>33</td></tr><tr><td>24</td><td>Turkey</td><td>RAB27A</td><td>2</td><td>MSD</td><td>BM</td><td>Flu, Melph,<br>ATG (RIC)</td><td>CSA, Cs</td><td>Intracerebral hemorrhage</td><td>Alive</td><td>68</td></tr><tr><td>25</td><td>Turkey</td><td>RAB27A</td><td>4</td><td>MSD</td><td>PBSC</td><td>NA</td><td>NA</td><td>–</td><td>Dead</td><td>–</td></tr><tr><td>26</td><td>Turkey</td><td>RAB27A</td><td>32</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>–</td><td>Alive</td><td>–</td></tr><tr><td>27</td><td>Kuwait</td><td>LYST</td><td>96</td><td>MSD</td><td>BM</td><td>Treo/Flu</td><td>CSA, MMF</td><td>–</td><td>Alive</td><td>100</td></tr><tr><td>28</td><td>Iran</td><td>LYST</td><td>62</td><td>MFD</td><td>BM</td><td>Flu, Melph,<br>ATG (RIC)</td><td>CSA, Cs</td><td>Acute GVHD (skin- stage II),<br>CMV reactivation,<br>hemorrhagic cystitis (due to<br>the BK virus), and PRES</td><td>Alive</td><td>28</td></tr><tr><td>29</td><td>Oman</td><td>LYST</td><td>41</td><td>Haploidentical</td><td>BM</td><td>Flu, Bu</td><td>Tacro</td><td>VOD, Pulmonary hemorrhage</td><td>Dead</td><td>1</td></tr><tr><td>30</td><td>Oman</td><td>LYST</td><td>10</td><td>MSD</td><td>PBSC</td><td>Flu, Bu, ATG</td><td>MTX, Tacro</td><td>–</td><td>Alive</td><td>25</td></tr><tr><td>31</td><td>Oman</td><td>LYST</td><td>60</td><td>SD</td><td>BM</td><td>Flu, Bu, ATG</td><td>MTX</td><td>–</td><td>Alive</td><td>396</td></tr><tr><td>32</td><td>Turkey</td><td>LYST</td><td>73</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>–</td><td>Dead</td><td>–</td></tr><tr><td>33</td><td>Kuwait</td><td>PRF1</td><td>150</td><td>MSD</td><td>BM</td><td>Flu, Bu, ATG</td><td>MTX</td><td>Acute kidney injury, chronic<br>enteropathy chronic gut and<br>kidney GVHD and thrombotic<br>microangiopathy</td><td>Dead</td><td>8</td></tr><tr><td>34</td><td>Jordan</td><td>PRF1</td><td>6</td><td>MSD</td><td>BM</td><td>Flu, Melph,<br>Thio</td><td>CSA, Cs</td><td>Intracerebral hemorrhage</td><td>Alive</td><td>6</td></tr><tr><td>35</td><td>Jordan</td><td>PRF1</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>–</td><td>Alive</td><td>–</td></tr><tr><td>36</td><td>Kuwait</td><td>STX11</td><td>8</td><td>MFD</td><td>BM</td><td>Bu, Cy, ATG</td><td>MTX</td><td>–</td><td>Alive</td><td>126</td></tr><tr><td>37</td><td>Iran</td><td>STXBP2</td><td>107</td><td>MSD</td><td>PBSC</td><td>Flu, Melph,<br>ATG (RIC)</td><td>CSA, Cs</td><td>Progressive persistent<br>pancytopenia and severe<br>hypocellular bone marrow,<br>methemoglobinemia, CMV<br>reactivation</td><td>Alive</td><td>46</td></tr><tr><td>38</td><td>UAE</td><td>UNC13D</td><td>18</td><td>MUD</td><td>NA</td><td>NA</td><td>NA</td><td>–</td><td>Alive</td><td>54</td></tr><tr><td>39</td><td>Kuwait</td><td>XIAP</td><td>36</td><td>MSD</td><td>BM</td><td>Flu, Bu</td><td>MTX</td><td>–</td><td>Dead</td><td>6</td></tr><tr><td>40</td><td>Oman</td><td>XIAP</td><td>126</td><td>Haploidentical</td><td>BM</td><td>Flu, Treo,<br>Thio</td><td>CSA, Cs</td><td>GVHD (GI)</td><td>Alive</td><td>39</td></tr><tr><td>41</td><td>Iran</td><td>SH2D1A</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>Dead</td><td>–</td></tr><tr><td>42</td><td>Turkey</td><td>TNFRSF9</td><td>144</td><td>MUD</td><td>PBSC</td><td>Flu, Melph,<br>Etoposide</td><td>Cs</td><td>HLH (It may be due to his<br>primary disease)</td><td>Dead</td><td>60</td></tr><tr><td>43</td><td>Turkey</td><td>TNFRSF9</td><td>27</td><td>MFD</td><td>BM</td><td>Flu, Melph,<br>ATG (RIC)</td><td>CSA, Cs</td><td>Sepsis, graft rejection</td><td>Dead<br>(Rejection,<br>COVID19)</td><td>15</td></tr><tr><td>44</td><td>Turkey</td><td>CD70</td><td>132</td><td>Haploidentical</td><td>BM</td><td>Flu, Bu, Thio</td><td>CSA, PTCy</td><td>Severe engraftment syndrome,<br>PJP (+166 days)</td><td>Dead (PJP)</td><td>14</td></tr><tr><td>45</td><td>Iran</td><td>IL10</td><td>7</td><td>MFD</td><td>BM</td><td>Flu, Melph, r-<br>ATG</td><td>CSA, MMF</td><td>GVHD (GI)</td><td>Alive</td><td>36</td></tr><tr><td>46</td><td>Turkey</td><td>IL10RB</td><td>16</td><td>MUD</td><td>BM</td><td>Flu, Melph</td><td>CSA</td><td>GVHD</td><td>Alive</td><td>66</td></tr><tr><td>47</td><td>Turkey</td><td>IL10RB</td><td>12</td><td>MMFD</td><td>BM</td><td>Flu, Bu, ATG</td><td>NA</td><td>–</td><td>Dead</td><td>0</td></tr><tr><td>48</td><td>Kuwait</td><td>FASLG</td><td>13</td><td>MSD</td><td>BM</td><td>Flu, Bu</td><td>MTX</td><td>–</td><td>Alive</td><td>113</td></tr><tr><td>49</td><td>Kuwait</td><td>FASLG</td><td>5</td><td>MUD</td><td>CB</td><td>Bu, Cy, ATG</td><td>MTX</td><td>–</td><td>Dead</td><td>1</td></tr></tbody></table>
M; male, F; female, MUD; matched unrelated donor, MFD; matched family donor, MSD; matched sibling donor, MMFD; mismatched family donor, MMUD; mismatched unrelated donor, r-ATG; rabbit antithymocyte globulin, CSA; Cyclosporine A, MTX; Methotrexate, Flu; fludarabine, MMF; mycophenolate mofetil, Bu; busulphan, Tacro; tacrolimus, Treo; treosulfan, Thio; thiotepa, Melph; melphalan, Cy; cyclophosphamide, PTCy; post-transplant cyclophosphamide, Cs; Corticosteroid, BM; bone marrow, PBSC; peripheral blood stem cell, CB; cord blood, MAC; myeloablative conditioning, RIC; reduced-intensity conditioning, GVHD; graft-versus-host disease, CMV; cytomegalovirus, GI; gastrointestinal, HLH; hemophagocytic lymphohistiocytosis, PJP; pneumocystis jiroveci pneumonia, VOD: veno-occlusive disease, PRES: posterior reversible encephalopathy syndrome.

<figure><img src="image_6.png" /><figcaption>**Fig. 4.** Survival analysis of monogenic immune dysregulation diseases patients in the MENA region. The best and worst survival belonged to syndromes with autoimmunity and normal DNT and Tregs and HLH with hypopigmentation, respectively.</figcaption></figure>

lowest median (IQR) age at the overall onset of symptoms [1 (1–2.5) months] and also infections [3 (1–5) months] and autoimmunity [3 (1–12) months]. The median (IQR) age of diagnosis and diagnosis delay were 17 (4–66) and 12 (4–65) months, respectively.

Diarrhea (8, 25%) and other non-respiratory tract infections (12, 37.5%) were most prevalent first presentations among 28 patients with available history. The most common clinical manifestations were infections (26, 83.9%) [abscess (17, 54.8%), chronic diarrhea (16, 51.6%), URTI (5, 16.1%)], autoimmunity (14, 45.2%) [IBD (8, 25.8%) and autoimmune enteropathy (6, 19.4%)], and atopy (5, 16.1%) [food alergy (3, 9.7%)].

Total lymphocyte counts were within the normal range for age in 11 (52.4%) and low in 7 (33.3%) patients. Most patients had normal neutrophil (12, 60%) and platelet (13, 61.9%) counts but low hemoglobin levels (18, 81.8%). Low CD3⁺T (12, 60%) and CD4⁺T (11, 55%), but normal CD8⁺T (15, 78.9%), CD19⁺B (9, 47.4%), and NK (10, 66.7%) cells were dominated the flowcytometry patterns. In the majority of patients, normal IgG (13, 61.9%), IgA (16, 80%), IgM (10, 52.6%), and IgE (10, 71.4%) were found. DNT and CD21low B cells were normal in three evaluated patients.

Patients underwent treatment with IgRT (4, 12.5%), corticosteroids (12, 37.5%), biologic immunosuppressives (10, 31.3%), and surgeries (2, 6.3%). HSCT was performed in 3 (9.4%) patients at 7, 12, and 16 months. At the end of the survey, 6 patients (22.2%) deceased mainly following sepsis (3, 50%).

## 4. Discussion

This is the largest published cohort of monogenic patients with immune dysregulation worldwide and the first comparative analysis among all subcategories of MIDDs. It is important to note that the prevalence of MIDD patients reported in the current MENA study may be an underestimation as some patients had died before the diagnosis or followed by hematology services. Only one systematic review complied 745 patients (186 articles), however they included heterogeneous monogenic defects associated with combined immunodeficiency and antibody deficiency as well as oligogenic patients in this review (only 197 patients have been classified correctly) [24].

In recent years, the development of multi-omics approaches has facilitated the diagnosis of a vast array of monogenic IEIs. For MIDDs, in
particular, next-generation sequencing has been associated with considerable diagnostic yields [25], as the clinical and immunological findings are highly variable and overlap with other subcategories of IEIs, making the clinical diagnosis more challenging for health care providers. The present study aimed to draw attention to demographic, clinical, immunological, and molecular characteristics of MIDD in MENA, a naïve geographical region.

In this cohort, the rate of parental consanguinity was exceptionally high (76%), explaining the emergence of such ultra-rare disorders often with autosomal recessive inheritance. The most common disease sub-category in this study population were syndromes with autoimmunity and Tregs defect but normal DNT cells (35%) and HLH with hypopigmentation (19.8%) and the most common defective genes were LRBA (23.9%), LYST (8.2%) and RAB27A (7.9%), all of which were primarily identified and studied in MENA region [26–28]. This pattern of distribution may reflect the impact of consanguineous marriage on the MENA-specific genetic signature. Considering the previously published systematic review on MIDD, besides LRBA deficiency (37.0%), mutations in non-autosomal recessive genes including FOXP3 (21.3%), AIRE (14.7%), and STAT3-GOF (12.1%) were the most common reported defects [24]. Our recent gene specific systematic reviews on most frequent MIDD also have shown that autosomal dominant and X-linked defects (e.g. 605 AIRE-deficient [29], 505 FAS-deficient [30], 312 FOXP3-deficient [31] 222 CTLA4-deficient [32] patients) were more prominent globally compared to frequent autosomal recessive defects (versus 212 LRBA-deficient [32,33], 190 IL10RA-deficient and 69 IL10RB-deficient [34] patients).

The clinical features were distinctive for each subcategory of MIDD, however, the most prevalent initial and overall manifestations of MIDD were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. The overall percentages of autoimmunity and lymphoproliferation were higher than their frequencies as initial manifestations which along with almost two-fold age of onset of autoimmunity and organomegaly (24 months) compared to infections (14.5 months), may represent chronicity of these manifestations and an essential need for follow-up of patients. Despite the limitation of inclusion criteria mentioned in the systematic review of MIDDs, infections (66%), autoimmunity (62%), lymphoproliferation (36%), allergy (4.5%), and malignancy (4%) were in the same range we observed in the current study from MENA region [24].

The infectious manifestation as initial symptoms of MIDD had a higher rate compared to another study on the MENA region, which reported non-infectious clinical manifestation as the core initial presentation in 97.2% of patients with mixed monogenic and non-monogenic immune dysregulation [19]. Nevertheless, the majority of patients (67.8%) still presented with non-infectious manifestations, highlighting the importance of considering these symptoms at the time of patient evaluation. In this regard, several studies have declared the inadequacy of 10 warning signs of IEI proposed three decades ago by Jeffery Modell Foundation for screening purposes [35,36]. In a recent study on 16,486 patients of the ESID registry, 68% of patients initially presented with isolated infections and an additional 9% with a combination of infectious and immune dysregulation symptoms. Around 25% of IEIs had expressed non-infectious manifestation at the beginning of the disease which may have been misleading for physicians exclusively relying on infection-centered warning signs [37].

Along with conventional treatment for IEIs, symptoms of MIDD might be amenable to HSCT which was performed for forty-nine (14.3%) patients of this cohort. This low rate of transplantation may stem from the lack of HSCT services in many MENA countries or death before the application of HSCT. Lower age at transplantation was associated with a better outcome, although the correlation was not significant (p = 0.141). Moreover, patients who were infused with stem cells from bone marrow sources and matched sibling donors had a more favorable outcome. Due to the small number of transplanted patients in this cohort and previous studies, no conclusions can be achieved based on the current results. In

this cohort, HSCT had the most favorable outcome in patients with RAB27A deficiency. A recent study evaluated factors influencing event-free survival (EFS) in IEI patients with almost two decades of follow-up and indicated transplantation age as one of the predictors for long-term EFS [38]. A recent comprehensive review has highlighted a better HSCT outcome for MIDDs including immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, CTLA4, and LRBA deficiencies if performed before an advanced stage of disease activity and prior to end-organ complications [31–33,39,40]. Some specific consideration also should be given to preparing patients with specific defects to improve HSCT outcomes. This includes the usage of JAK inhibitors to reduce disease activity in patients with STAT1/STAT3-GOF and the usage of reduced toxicity myeloablative conditioning and serotherapy due to intestinal complications in patients with IL10/IL10R defects [34,39,41]. Of note, in the latest EBMT/ESID inborn errors working party guideline for immune dysregulation disorders no significant correlation between conditioning, donor type, and age at transplant with the outcome has been stated [42]. Therefore, further studies should investigate the benefits and specifications of transplantation for MIDDs.

## Funding statement

This work was supported by the vice chancellor for research, Alborz University of Medical Sciences.

## Declaration of Competing Interest

The authors have no conflicts of interest to declare that are relevant to the content of this article.

## Data availability

Data will be made available on request.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.clim.2022.109131.

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