Front. Cell. Infect. Microbiol. Frontiers in Cellular and Infection Microbiology Front. Cell. Infect. Microbiol. 2235-2988 Frontiers Media S.A. 10.3389/fcimb.2025.1615929 Cellular and Infection Microbiology Review Clinical features of patients with fungal infections caused by CARD9 deficiency: a literature review of case reports Tang Congchen 1 † Liu Yalan 1 † Long Jiangchao 2 Lv Xiaoju 1 * 1 Center for Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China 2 Intensive Care Unit, People’s Hospital of Dafang, Bijie, Guizhou, China

Edited by: Andrew L. Snow, Uniformed Services University of the Health Sciences, United States

Reviewed by: Anne Puel, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Rabab Elsayed El Hawary, Cairo University, Egypt

Donald C. Vinh, McGill University Health Centre, Canada

*Correspondence: Xiaoju Lv, lvxj@scu.edu.cn

†These authors have contributed equally to this work and share first authorship

 16 07 2025 2025 15 1615929 07 05 2025 30 06 2025 Copyright © 2025 Tang, Liu, Long and Lv 2025 Tang, Liu, Long and Lv

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Caspase recruitment domain containing protein 9 (CARD9) deficiency is an autosomal-recessive primary immunodeficiency disorder, undermines the body’s capacity to combat fungal infections. In recent years, the number of reported cases of fungal infections associated with CARD9 deficiency has been increasing. This study undertook a systematic review of case reports, incorporating 89 patients with CARD9 deficiency complicated by fungal infections. The findings demonstrated that the patient population predominantly consisted of young and middle-aged individuals (33.43 ± 19.12 years, range: 1-91), and the majority (52 patients, 58.43%) developed the disease during childhood or adolescence. Significant geographical variations were observed in the distribution of gene mutations. Specifically, the c.820dupG mutation was predominantly found in East Asia, while the c.865C>T mutation was primarily found North Africa. Regarding the clinical manifestations, the most frequently affected sites were the skin, central nervous system, and lymph nodes, and the principal fungal pathogens identified were Trichophyton and Candida. Correlation analysis indicated that c.883C>T increased the likelihood of Candida infection (p=0.008, OR=10.421, 95% CI 1.849-58.748), c.865C>T increased the probability of Trichophyton infection (p=0.038, OR=5.760, 95% CI 1.098-30.217) and dematiaceous fungi infection (p=0.005, OR=9.653, 95% CI 2.019-46.153). According to the types of mutations, nonsense mutation increased the risk of dematiaceous fungi infection (p=0.014, OR=6.212, 95% CI 1.453-26.556). Notably, a proportion of patients succumbed to the disease, and this was predominantly associated with infections of the central nervous system, blood system, and viscera. This underscores the importance of adequate antifungal therapy and long-term follow-up for patients with CARD9 deficiency-related fungal infections.

 CARD9 deficiency fungal infection gene mutation clinical features review section-in-acceptance Clinical Infectious Diseases Introduction

CARD9 is a crucial adaptor protein in the innate immune response against fungal infections and its Online Mendelian Inheritance in Man (OMIM) number is 607212. Autosomal recessive CARD9 deficiency was first documented in 2009 within a consanguineous Iranian pedigree presenting with chronic mucocutaneous candidiasis (CMC) and dermatophytosis (Glocker et al., 2009). When the immune system detects fungal pathogens, CARD9 plays a pivotal role in the activated signaling pathways (Yazdi et al., 2023). Mutations in the CARD9 gene (NM_052813) result in CARD9 deficiency, which substantially compromises the body’s capacity to elicit an effective antifungal immune response. This disruption targets mechanisms primarily mediated by the C-type lectin receptor (CLR) and Toll-like receptor (TLR) families, which initiate defense responses against fungal pathogens (Drummond et al., 2018; Doron et al., 2021). In recent years, the number of reported cases of fungal infections associated with CARD9 deficiency has been gradually increasing. These infections present diverse clinical manifestations and can affect multiple organs and systems in the human body. Understanding the clinical features of patients with CARD9 deficiency-related fungal infections is of great significance for early diagnosis, appropriate treatment, and improving patient prognosis. However, due to the relatively rare study of CARD9 deficiency and the wide variety of fungal pathogens involved, the current comprehensive understanding of its clinical characteristics remains limited. Previous studies have been fragmented, and it is necessary to conduct a systematic review of case reports to summarize and analyze the existing data. This review aims to provide more perspectives by collecting and analyzing case reports from around the world. By systematically examining the clinical features, gene mutations, treatment strategies, and prognoses of patients with CARD9 deficiency-related fungal infections, we hope to provide valuable insights for clinicians and researchers in the fields of infectious diseases and immunology, facilitating better management of these complex cases.

 Materials and methods Literature search

The review process entailed a comprehensive exploration of all extant published literature on reported cases of fungal infections attributable to CARD9 deficiency. In the pursuit of relevant published works, a systematic search was conducted across the PubMed and China National Knowledge Infrastructure (CNKI) databases. The search terms employed were “CARD9”, “caspase recruitment domain deficiency” and “caspase recruitment domain containing protein 9”. Subsequently, the references of the initially selected papers underwent meticulous examination and screening. Articles of a review nature, those lacking detailed clinical data, and reports concerning patients without fungal infections were meticulously excluded from the analysis.

 Data extraction

The following data were extracted: publication year, first author, age of the patient at the time of reporting, age of onset of the patient, patient’s gender, site of infection, fungal culture results, mutation sites, treatment regimens, treatment outcomes, whether the patient died of the disease, and patient origin. According to Melanized Fungi in Human Disease (Revankar and Sutton, 2010), the dematiaceous fungi category was extracted. According to Fungal Infection: Diagnosis and Management, Fourth Edition (Fsbath, 2012), superficial fungal infections are defined as only infections confined to the outermost layers of the skin, nails, hair, and mucous membranes. Deep fungal infections include the subcutaneous mycoses and the systemic mycoses, defined as infections of the dermis, subcutaneous tissues, and adjacent bones, as well as infections involving internal organs and vital structures. Define invasive fungal infection according to the Consensus Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (Donnelly et al., 2020). We distinguish the types of gene mutations through https://www.ncbi.nlm.nih.gov/clinvar.

Regarding the treatment outcomes, a subjective classification was employed, categorizing them into five distinct groups. The “not reported” category encompassed cases where treatment outcome information was unavailable. The “ineffective” category denoted cases in which, following systematic treatment, the patient’s general condition and the results of auxiliary examinations exhibited no signs of improvement. The “slightly improved” category referred to cases showing some degree of improvement, yet with a low likelihood of achieving complete clinical remission. The “partially improved” category applied to cases demonstrating improvement and a relatively high probability of attaining complete clinical remission. Finally, the “complete clinical remission” category signified cases where the patient’s fungal infection was eradicated, and organ functions were essentially restored.

 Statistical analysis

The data extracted from the study were analyzed by the SPSS 27.0 software. The Mantel-Haenszel test was used to analyze the association between different factors, with sex as the stratification factor. When the sample size (n) is≥40 and all the theoretical count under the null hypothesis (T) are≥5, choose the Pearson chi-square test. When n≥40 and at least one theoretical count meets 1≤T<5, use the continuity-corrected chi-square test (Yates’ correction). When n<40 or T<1, select Fisher’s exact test. To explore further correlations, univariate and multivariate binary logistic regression analysis were conducted. In the multivariate regression analysis, we included age, gender, and different pathogens to eliminate confounding. The outcomes of this analysis were presented in terms of odds ratios (ORs) and their corresponding 95% confidence intervals (CIs).

 Results Patient basic information

In this study, a total of 58 articles were comprehensively incorporated, involving 89 patients with CARD9 deficiency, as detailed in Table 1 . Among them, 48 patients were male (56.18%). The reported average age was 33.82 ± 18.90 years (range: 1-91), and 52 patients (58.43%) whose age of onset was less than 18 years old. The patients in this study originated from 17 distinct countries. As depicted in Figure 1 , the countries with the highest 3 number of cases were China (34 cases, 38.20%), Algeria (12 cases, 13.48%), and Iran (10 cases, 11.24%).

Statistical summary of the 82 enrolled patients’ information.

Patient Kindreds Reportd age Onset age Gender Site of infection Fungal culture results Mutation site Type of mutation Other genetic mutation Method of genetic testing Treatment Outcome Death Patient origin References
P1 Kindred 1 19 3 Male Oral cavity Candida Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing KTCZ Complete clinical remission No Iran (Glocker et al., 2009)
P2 Kindred 1 – <18 Male Oral cavity, CNS Candida Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing – Ineffective Yes Iran (Glocker et al., 2009)
P3 Kindred 1 50 42 Female Skin, vagina Candida albicans Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing – – No Iran (Glocker et al., 2009)
P4 Kindred 1 – – Female Oral cavity, vagina, skin Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing – – No Iran (Glocker et al., 2009)
P5 Kindred 1 – <18 Male Skin - Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing – – No Iran (Glocker et al., 2009)
P6 Kindred 1 – <18 Female Oral cavity, CNS - Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing – – Yes Iran (Glocker et al., 2009)
P7 Kindred 1 – <18 Female Oral cavity, CNS Candida Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing – Ineffective Yes Iran (Glocker et al., 2009)
P8 Kindred 2 75 6 Male Skin, Scalp, Nails, Lymph nodes Trichophyton violaceum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Algeria (Lanternier et al., 2013)
P9 Kindred 2 29 2 Male Skin, Scalp, Nails, Lymph nodes, CNS Trichophyton violaceum – – Not found Sanger sequencing GF+KTCZ+ITZ Ineffective Yes Algeria (Lanternier et al., 2013)
P10 – 40 9 Female Skin, Scalp, Nails, Lymph nodes Trichophyton rubrum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Algeria (Lanternier et al., 2013)
P11 Kindred 3 56 8 Male Skin, Scalp, Nails Trichophyton violaceum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Algeria (Lanternier et al., 2013)
P12 Kindred 3 34 8 Male Skin, Scalp, Nails, Lymph nodes Trichophyton violaceum – – Not found Sanger sequencing – – Yes Algeria (Lanternier et al., 2013)
P13 Kindred 3 41 8 Female Nails Trichophyton violaceum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Algeria (Lanternier et al., 2013)
P14 Kindred 4 43 19 Male Skin, Scalp, Nails, Lymph nodes - Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Algeria (Lanternier et al., 2013)
P15 Kindred 4 40 21 Male Skin, Perineum, Scalp, Lymph nodes - Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Algeria (Lanternier et al., 2013)
P16 Kindred 4 28 – Male Skin, Scalp - – – Not found Sanger sequencing – – Yes Algeria (Lanternier et al., 2013)
P17 Kindred 5 39 – Male Skin, Scalp, Lymph nodes Trichophyton violaceum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing GF+KTCZ Partially improved Yes Algeria (Lanternier et al., 2013)
P18 Kindred 5 37 – Female Nails, Skin - Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Algeria (Lanternier et al., 2013)
P19 Kindred 6 40 – Male Skin, Bone, Lymph nodes Trichophyton rubrum Homozygous c.301C>T (p.Arg101Cys) Missense Not found Sanger sequencing – – No Morocco (Lanternier et al., 2013)
P20 Kindred 6 49 – Female Scalp, Nails - Homozygous c.301C>T (p.Arg101Cys) Missense Not found Sanger sequencing – – Yes Morocco (Lanternier et al., 2013)
P21 Kindred 7 91 6 Male Skin, Scalp, Nails - Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Tunisia (Lanternier et al., 2013)
P22 Kindred 7 44 12 Male Scalp, Nails Trichophyton rubrum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Tunisia (Lanternier et al., 2013)
P23 Kindred 7 52 5 Female Skin, Scalp, Nails, Lymph nodes Trichophyton rubrum and Trichophyton violaceum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Tunisia (Lanternier et al., 2013)
P24 – 62 6 Male Skin, Scalp, Nails, Lymph nodes Trichophyton rubrum and Trichophyton violaceum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing – – No Tunisia (Lanternier et al., 2013)
P25 – 41 30 Male CNS Candida albicans Homozygous c.271T>C (p.Tyr91His) Missense Not found Whole exome sequencing GM-CSF+VRC Complete clinical remission No France (Gavino et al., 2014)
P26 – 21 13 Male Skin - Compound c.191_192insTGCT (p. Leu64fsTer59) and c.472C>T (p.Gln158Ter) Frameshift and nonsense Not found Whole exome sequencing ITZ+AMB Ineffective No China (Wang et al., 2014)
P27 – 17 6 Male Skin - Homozygous c.819_820insG(p.Asp274fsTer60) Frameshift Not found Whole exome sequencing ITZ+AMB Partially improved, relapse after discontinuation of the drug No China (Wang et al., 2014)
P28 – 43 20 Female Skin - Homozygous c.819_820insG(p.Asp274fsTer60) Frameshift Not found Sanger sequencing Surgical operation+ITZ Partially improved No China (Wang et al., 2014)
P29 – 64 48 Male Skin - Homozygous c.819_820insG(p.Asp274fsTer60) Frameshift Not found Sanger sequencing ITZ+TBF Partially improved No China (Wang et al., 2014)
P30 – 24 3 Male Skin, Oral cavity, Scalp, Nails Trichophyton mentagrophytes Homozygous c.302G>T (p. Arg101Leu) Missense Not found Sanger sequencing KTZ, ITZ, TBF, AMB Slightly improved No Italy Anete2015 (Grumach et al., 2015)
P31 – 4 1.5 Female CNS Candida albicans Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing AMB+5-FC+VRC followed by long-term FCZ Complete clinical remission No Turkey (Herbst et al., 2015)
P32 – 40 13 Male Skin Trichophyton rubrum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing POS Complete clinical remission No Egypt (Jachiet et al., 2015)
P33 – 8 5 Female CNS, Liver, Exophiala dermatitidis Homozygous c.52C>T (p. Arg18Trp) Missense Not found Sanger sequencing AMB+VRC Ineffective – France (Lanternier et al., 2015a)
P34 – 26 18 Female Bone, Skin, Lung Exophiala spinifera Homozygous c.967_969delGAG (p. Glu323de) Deletion Not found Sanger sequencing – – – Iran (Lanternier et al., 2015a)
P35 – 42 36 Female CNS, Vagina, Candida albicans Homozygous c.208C>T (p. Arg70Trp) Missense Not found Sanger sequencing AMB +5-FC followed by long-term FCZ Complete clinical remission No Turkey (Lanternier et al., 2015b)
P36 – 7 7 Female Skin, CNS, Oral cavity, Nails Candida albicans Homozygous c.208C>T (p. Arg70Trp) Missense Not found Sanger sequencing AMB +FCZ Partially improved No Turkey (Lanternier et al., 2015b)
P37 – 28 17 Male Colon, Ileum, CNS, Candida glabrata Homozygous c.104G>A (p. Arg35Gln) Missense Not found Sanger sequencing FCZ, ITZ Ineffective No Iran (Lanternier et al., 2015b)
P38 – 37 34 Female CNS, Oral cavity, Candida albicans Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing AMB and 5-FC followed by long-term FCZ Complete clinical remission No Morocco (Lanternier et al., 2015b)
P39 – 34 26 Male Oral cavity, Esophagus, Colon Candida albicans Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing AMB+POS Slightly improved No Pakistan (Lanternier et al., 2015b)
P40 – 25 3 Male CNS, Oral cavity, Skin Candida albicans Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Targeted Resequencing FCZ+AMB+CAS+G-CSF followed by long-term FCZ Complete clinical remission No Turkey (Celmeli et al., 2016)
P41 – 25 25 Female Eye, Bone, Vagina Candida albicans Compound c.1138G>C (p. Ala380Pro) and c.951G>A (p.Arg317Arg) Missense+ Silent Not found Whole exome sequencing High-dose systemic antifungal agents followed by long-term KTZ Partially improved No Britain (Jones et al., 2016)
P42 – 45 9 Male CNS, Oral cavity, Abdominal cavity, Liver, Lymph nodes Aspergillus, Candida. Homozygous c.883C>T (p.Gln295Ter) Nonsense SPAST mutation Whole exome sequencing Long-term KTZ Complete clinical remission No Europe (Rieber et al., 2016)
P43 – 12 12 Male Blood vessel, Abdominal cavity, Skin Aspergillus fumigatus Homozygous c.3G>C (p. Met1Ile) Missense Not found Targeted sequencing Antifungal drug treatment +surgical operation+double umbilical cord stem cell transplantation Ineffective Yes Africa (Rieber et al., 2016)
P44 – 37 35 Female Skin, Lymph nodes, Oral cavity Corynespora cassiicola Homozygous c.191_192InsTGCT(p. Leu64fsTer59) Frameshift Not found Whole exome sequencing AMB Slightly improved No China (Yan et al., 2016)
P45 – 47 10 Female Skin, Scalp, Lymph nodes, CNS Trichophyton rubrum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing Long-term ITZ Complete clinical remission No Algeria (Boudghene Stambouli et al., 2017)
P46 – 34 16 Female Skin, Oral cavity, CNS Phialophora verrucosa Compound c.104>A (p. Arg35Gln)+c.241G>A (p. Glu81Lys) Missense Not found Sanger sequencing GM-CSF+ITZ+TBF Slightly improved No China (Zhang et al., 2017)
P47 – 17 7 Female CNS, Lung, Oral cavity Candida albicans Compound c.883C>T (p.Gln295Ter) Nonsense+ Missense Heterozygote NLRP12 mutation (c.910C>T; p.His304Tyr) Targeted sequencing VRC+AMB Ineffective Yes Turkey (Cetinkaya et al., 2018)
P48 – 8 8 Female Colon Prototheca zopfii Homozygous c.781delG (p. Val261fs). Frameshift Not found Whole exome sequencing AMB Partially improved No Turkey (Sari et al., 2018)
P49 – 58 43 Female Eye, CNS Candida albicans Compound c.184G>A and c.288C>T Intronic (splicing) Not found Sanger sequencing Long-term VRC Complete clinical remission No Canada (Gavino et al., 2018)
P50 – 28 26 Male Skin Phialophora americana Homozygous c.819_820insG(p.Asp274fsTer60) Frameshift Not found Sanger sequencing ITZ+TBF – No China (Huang et al., 2019)
P51 – 24 12 Male Skin, Esophagus, Bone Trichosporon asahii, Candida albicans Homozygous c.819_820insG(p.Asp274fsTer60) Frameshift Not found Sanger sequencing Long-term VRC Complete clinical remission No China (Quan et al., 2019)
P52 – 23 23 Male CNS, Skin, Lymph nodes Exophiala dermatitidis Homozygous c.759dup (p. Lys254GlufsTer81) Frameshift Not found Sanger sequencing AMB +VRC Ineffective Yes China (Wang C. et al., 2019)
P53 – 35 17 Female Skin, Lymph nodes, CNS Pallidocercospora crystallina Homozygous c.1118G>C (p. Arg373Pro) Missense Not found Whole exome sequencing ITZ+TBF+ surgical operation Complete clinical remission No China (Guo et al., 2019)
P54 – 7 5 Female Oral cavity, Nails, CNS Candida albicans Homozygous c.208C>T (p. Arg70Trp) Missense Not found Sanger sequencing AMB + long-term FCZ Complete clinical remission No Turkey (Martin et al., 2019)
P55 – 46 46 Female Skin Mucor irregularis Compound c.692C>T (p. p.Ser231Phe) and c.905_907delTCT (p.Ser302del) Missense+ Frameshift Not found Sanger sequencing AMB + long-term ITZ Complete clinical remission No China (Wang X. et al., 2019)
P56 – 27 16 Female Skin Microsporum ferrugineum Compound c.883C>T (p.Gln295Ter) and c.1118G>C(p.Arg373Pro) Nonsense+ Missense Not found Sanger sequencing ITZ+TBF Partially improved No China (Zhang et al., 2019)
P57 – 10 9 Male CNS, Oral cavity, Liver Candida albicans Homozygous c.819_820insG(p.Asp274fsTer60) Frameshift Not found Whole exome sequencing G–CSF+FCZ+5-FC Complete clinical remission No China (Du et al., 2020)
P58 – 12 9 Male Colon, Esophagus, Oral cavity Histoplasma capsulatum Compound c.1204_1205insC (p. Cys402SerfsTer2) and c.1118G>C (p.Arg373Pro) Frameshift+ Missense Not found Targeted sequencing AMB followed by ITZ Complete clinical remission No China (Gao et al., 2020)
P59 – 31 16 Male Skin, Nails, Lymph nodes Trichophyton rubrum, Trichophyton violaceum, Aspergillus fumigatus, and Aspergillus flavus. Compound c.271T>C (p.Tyr91His) and c.1269 + 18G>A Missense+ Intronic STS gene (Xp22.3) Targeted sequencing G-CSF+GM-CSF+ multiple antifungal drugs Slightly improved, recurrent episodes No The United States of America (Nazarian et al., 2020)
P60 – 56 32 Female Skin, Lymph nodes, Lung Aspergillus nomius, Exophiala spinifera Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Sanger sequencing Recombinant interferon γ-1b+ multiple antifungal drugs Ineffective Yes Argentina (Perez et al., 2020)
P61 – 48 17 Male Skin Trichophyton rubrum, Candida albicans, Mucor irregularis Compound c.184 + 5G>T and c.951G>A (p.Arg317Arg) Intronic (Splice) Not found Whole exome sequencing ITZ+TBF Complete clinical remission No China (Wang X. et al., 2020)
P62 – 55 30 Female Skin Phialophora expanda Homozygous c.819_820insG (p.Asp274fsTer60) Frameshift Not found – AMB+ITZ Complete clinical remission No China (Huang et al., 2020)
P63 – <1 <1 Male Lung, Liver, Skin, Spleen, Lymph nodes Talaromyces marneffei Compound c.1118G>C (p. Arg373pro) and c.610C>T (p.Asp204Asp) Missense+ Silent Not found Whole exome sequencing VRC Complete clinical remission No China (Ba et al., 2021)
P64 – 32 27 Male Skin, Nails, Scalp, Lymph nodes Trichophyton rubrum Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found – ITZ Partially improved, relapse after discontinuation of the drug No Spain (Benmehidi et al., 2021)
P65 – 4 4 Female CNS, Spleen, Lymph nodes Exophiala dermatitidis Compound c.586A>G (p. Lys196Glu) and c.1118G>C (p.Arg373Pro) Missense+Missense Not found Targetedsequencing AMB+VRC followed by TBF Complete clinical remission No Japan (Imanaka et al., 2021)
P66 – 26 17 Female Skin Exserohilum rostratum c.1108C>T (p.Gln370Ter) Nonsense Not found Targetedsequencing ITZ+5-FC Complete clinical remission No India (Kalantri et al., 2021)
P67 – 37 <18 Male CNS, Skin, Oral cavity Candida albicans Homozygous c.883C>T (p.Gln295Ter) Nonsense Not found Sanger sequencing Multiple antifungal drugs Ineffective Yes Turkey (Kuruoğlu et al., 2021)
P68 – 6 6 Male CNS Alternaria Compound c. 1526G>A (p.Arg509Lys) and c.586A>G (p.Lys196Glu) Missense+Missense Not found Whole exome sequencing Surgical operation+ VRC+ AMB followed by long term VRC Complete clinical remission No China (Lai et al., 2021)
P69 – 5 5 Male Lung, Liver, Spleen, Abdominal cavity, Bone marrow, Talaromyces marneffei Compound c.440T>C(p.Leu147Pro) and c.586A>G(p.Lys196Glu) Missense+Missense Not found Medical Exome Sequencing AMB+VRC Ineffective Yes China (You et al., 2021)
P70 – 55 23 Female Skin Phialophora Homozygous c.819_820insG(p.Asp274fsTer60) Frameshift Not found Exome Sequencing AMB+ITZ Partially improved No China (Huang et al., 2022a)
P71 – 30 25 Male Skin, Liver Trichosporon asahii Homozygous c.819_820insG(p.Asp274fsTer60) Frameshift Not found – VRC Partially improved No China (Huang et al., 2022b)
P72 – 28 23 Female Skin, Nasal cavity, CNS Alternaria infectoria Homozygous c.865C>T (p.Gln289Ter) Nonsense Not found Candidate Gene Sequencing AMB+ITZ Complete clinical remission No Turkey (Paccoud et al., 2022)
P73 – 38 28 Male Skin Trichophyton tonsurans Heterozygote c.596A>R (p. Lys196Glu) Missense Not found Sanger sequencing POS Complete clinical remission No China (Tan et al., 2022)
P74 – 68 67 Male Skin, Lung, Corynespora cassiicola, Cladosporium Compound c.106C>T (p.Gln36Ter) and c.1118G>C (p.Arg373Pro) Missense+Missense Not found Whole exome sequencing VRC Complete clinical remission No China (Wang et al., 2022)
P75 – 6 5 Male Lung, Spleen, Lymph nodes, Rectum, Colon, Bone marrow Talaromyces marneffei Heterozygote c.820dupG (p. Asp274Ter) Frameshift CD40LG mutation (c.346G>A) Whole exome sequencing VRC+AMB Slightly improved No China (Yan et al., 2022)
P76 – 21 20 Female Urethra Candida glabrata c.808-11G>I Intronic Not found Whole exome sequencing VRC, MFG, CAS Complete clinical remission, relapse after discontinuation of the drug No China (Deng et al., 2023)
P77 – 23 <18 Male Skin, Lymph nodes, Parotid gland Trichophyton rubrum, Microsporum canis – – Not found – Surgical operation+ GF Complete clinical remission No Morocco (El Maati et al., 2023)
P78 – 14 12 Female Lung Aspergillus terreus Homozygous c.86G>A (p. Arg29His) Missense Not found Whole exome sequencing Long term VRC Complete clinical remission No Iran (Fallahi et al., 2023)
P79 – 17 16 Male Skin, CNS Prototheca wickerhamii c.820dupG (p. Asp274fs) Frameshift Not found – VRC+AMB Partially improved No China (Feng et al., 2023)
P80 – 40 40 Female Skin, Lymph nodes Purpureocillium lilacinum Homozygous c.820dupG(p.Asp274fs) Frameshift Not found – VRC Complete clinical remission No Japan (Majima et al., 2023)
P81 – 12 12 Male CNS, Oral cavity Candida albicans Compound c.1118G>C (p.Arg373Pro) and c.951G>A (p.Arg317Arg) Missense+ Silent Not found Whole exome sequencing AMB+VRC+5-FC followed by VRC+5-FC Complete clinical remission No China (Wang et al., 2023)
P82 – 29 25 Male Skin Phialophora verrucosa Compound c.1118G>C (p.Arg373Pro) and c.820_821insG (p.Asp274fsTer60) Missense+ Frameshift Not found Sanger sequencing POS Partially improved, relapse after discontinuation of the drug No China (Zhang L. et al., 2023)
P83 – 66 59 Female Skin Fusarium solaniae, Mucor irregularis Homozygous c.491delT Frameshift Not found Whole exome sequencing AMB Complete clinical remission No China (Zhou et al., 2023)
P84 – 21 13 Female Skin, Lung Trichosporon asahii Homozygous c.820dupG (p. Asp274fs) Frameshift Not found Exome Sequencing VRC followed by ITZ – – China (Chen et al., 2023)
P85 – 41 16 Female Skin Fusarium verticillioides Homozygous c.819_820insG (p.Asp274fsTer60) Frameshift Not found Whole exome sequencing ITZ Complete clinical remission No China (Zhang W. et al., 2023)
P86 – 80 77 Male Skin, Lymph nodes Trichophyton rubrum Homozygous c.586A>G (p. Lys196Glu) Missense Not found Whole exome sequencing Surgical operation+ long term ITZ Complete clinical remission No Japan (Ansai et al., 2024)
P87 – 63 63 Male Blood, Abdominal cavity T. marneffei c.35G>A (p.Ser12Asn) Missense Not found Whole exome sequencing CAS+VRC+AMB Ineffective Yes China (Liang et al., 2024)
P88 – 6 2 Female CNS Exophiala dermatitidis Homozygous c.820dupG (p. D274GfsX60) Frameshift Not found Whole exome sequencing VRC+5-FC+AMB Ineffective Yes China (Ma et al., 2024)
P89 – 24 24 Female CNS Candida albicans Homozygous c.184 + 5G>T Intronic Not found Whole exome sequencing CAS followed by FCZ+5-FC Complete clinical remission No China (Zhou et al., 2024)

CNS, Central Nervous System; VRC, Voriconazole; ITZ, Itraconazole; AMB, Amphotericin B; TBF, Terbinafine; FCZ; POS, Posaconazole; CAS, Caspofungin; FCZ, Fluconazole;5-FC, 5 - Fluorocytosine; GF, Griseofulvin; MFG, Micafungin; KTCZ, Ketoconazole; G-CSF, Granulocyte Colony Stimulating Factor; GM-CSF, Granulocyte Macrophage Colony Stimulating Factor.

The origins of all patients.

Pie chart showing the origins of patients from various countries. China has the largest segment at 34, followed by the United States with 12, India with 10, and Algeria with 9. Other countries have smaller segments, each representing fewer patients. Gene variation distribution

As illustrated in Figure 2 , this article comprehensively encompasses a total of 38 CARD9 gene mutations. The 5 most frequently occurring mutations are as follows: c.865C>T (18 cases), c.883C>T (14 cases), c.819-820insG (12 cases), c.1118G>C (9 cases) and c.820dupG (5 cases). The “others” segment in Figure 2 encompasses 27 distinct gene mutations, each with a frequency of only one instance. These mutations are c.472C>T, c.302G>T, c.52C>T, c.967_969delGAG,c.1138G>C,c.3G>C,c.241G>A,c.781delG,c.184G>A,c.288C>T,c.759dup,c.692C>T,c.905_907delTCT,c.1204_1205insC,c.1269 + 18G>A,c.610C>T, c.1108C>T, c.1526G>A, c.440T>C, c.596A>R, c.106C>T, c.808-11G>I, c.86G>A, c.491delT, and c.35G>A. The CARD9 gene and related gene mutations are shown in Figure 3 . There are 6 types of gene mutations: nonsense (30 cases), missense (29 cases), frameshift (23 cases), deletion (1 cases), silent (2 cases), and intronic (6 cases) mutation.

Distribution of gene mutations.

Pie chart showing the distribution of gene mutations. The largest segment is labeled “Others” at 24.3%, followed by c.865C>T at 17.5%, c.883C>T at 13.6%, c.819_820insG at 11.7%, and c.1118G>C at 8.7%. Other smaller segments represent various mutations with percentages ranging from 4.9% to 1.9%.

Schematic diagram of CARD9 gene mutations (intronic mutations represented by gene changes, other mutations denoted by amino acid changes. I to XIII = exons of CARD9, Coding DNA Sequence:155-1765).

Schematic diagram of CARD9 gene mutations highlighting various mutation points across regions labeled one to thirteen. Mutations include Arg18Trp, Tyr91His, Gln158Ter, among others, with specific nucleotide changes indicated. Clinical features

This study enrolled patients with fungal infections involving 18 distinct anatomical sites, as depicted in Figure 4 . All patients had deep infections. Among them, 32.82% were invasive infections and 67.18% were non-invasive infections. The 3 most commonly affected sites were the skin, central nervous system, and lymph nodes. In terms of taxonomic classification at the genus level, Trichophyton and Candida were the 2 most prevalent pathogens, as illustrated in Figure 5 . Dematiaceous fungi (16 cases) including: Exophiala, Phialophora, Corynespora, Exserohilum, Alternaria, and Cladosporium. In addition to standard antifungal pharmacotherapy, diverse treatment modalities were employed. Colony-stimulating factor (CSF) was administered to 5 patients (P18, P33, P39, P50, P52), surgical interventions were performed on 6 patients (P21, P36, P46, P61, P70, P79), and 1 patient (P53) received recombinant interferon γ-1b treatment. According to the clinical outcomes, they were classified into the following 5 categories: not reported (22 cases, 24.71%), ineffective (14 cases, 15.73%), slightly improved (6 cases, 6.74%), partially improved (13 cases, 14.61%), and complete clinical remission (34 cases,38.20%). Unfortunately, 16 patients (17.98%) succumbed to the disease.

Site of infections.

Circular chart depicting sites of infections categorized as invasive and non-invasive. Non-invasive infections include oral cavity, scalp, and nails, shown in blue and other colors. Invasive infections like central nervous system and lungs are in green. A legend indicates the number of patients with color codes ranging from 1 to over 52.

Distribution of fungal pathogens.

Circular chart illustrating the distribution of fungal pathogens. The chart features segments representing different pathogens, such as Candida, Trichophyton, and Aspergillus, with varying shades indicating their prevalence. A color legend at the bottom denotes prevalence ranges from one to sixteen. The relationship among genes, fungal pathogens and infection sites

To explore the relationships among various factors, we included the top 5 most frequent gene mutations (c.865C>T, c.819_820insG, c.1118G>C, c.883C>T, c.820dupG), gene mutations not in the top 5 (other mutations), Trichophyton, Candida, dematiaceous fungi, the top 3 most frequent anatomical sites (skin, CNS, lymph nodes), as well as invasive infections in the data analysis. Initially, the Mantel-Haenszel test was employed to assess the relationships between these factors. This statistical approach identified 18 significant associations, as detailed in Table 2 : c.865C>T and Trichophyton, c.865C>T and dematiaceous fungi, c.865C>T and skin, c.865C>T and lymph nodes, c.865C>T and invasive infections, c.819_820insG and Trichophyton, c.819_820insG and lymph nodes, c.883C>T and Candida, other mutations and Candida, other mutations and skin, other mutations and central nervous system, other mutations and invasive infections, nonsense mutation and dematiaceous fungi, missense mutation and dematiaceous fungi, missense mutation and skin, missense mutation and invasive infections, frameshift mutation and Trichophyton, frameshift mutation and dematiaceous fungi. Subsequently, binary logistic regression analysis was carried out on these 19 identified associations to further quantify the relationships and estimate the strength of the associations, as presented in Table 3 . The results indicated that c.883C>T increased the likelihood of Candida infections(p=0.008, OR=10.421, 95% CI 1.849-58.748), c.865C>T increased the probability of Trichophyton infections (p=0.038, OR=5.760, 95% CI 1.098-30.217) and dematiaceous fungi (p=0.005, OR=9.653, 95% CI 2.019-46.153). According to the types of mutation, nonsense mutation increased the risk of dematiaceous fungi infections (p=0.014, OR=6.212, 95% CI 1.453-26.556).

The relationship between genes and infections.

Total patients (N=82) Trichophyton (n=20) Candida (n=18) Dematiaceous fungi (n=16) Skin (n=52) Central nervous system (n=26) Lymph nodes (n=24) Invasive infection (n=44)
Site of mutation/P-value
c.865C>T (n=18) <0.001 b 0.114b <0.001 b 0.047 a 0.121a 0.006 a 0.002 a
c.819_820insG (n=12) 0.033 b 0.919b 0.147b 0.220b 0.381b 0.039 b 0.126a
c.1118G>C (n=8) 0.208b 0.818b 0.319b 1.000b 1.000b 0.897b 0.368b
c.883C>T (n=14) 0.267b 0.005 b 0.388b 0.072a 0.068b 0.634b 0.167b
c.820dupG (n=5) 0.439b 0.505b 0.580b 0.520b 1.000b 0.970b 0.450b
Other Mutations (n=42) 0.739a 0.042 a 0.150b 0.004 a 0.036 a 0.222a 0.027 b
Type of mutation/P-value
Nonsense(n=26) 0.059a 0.349a 0.004 a 0.692a 0.908a 0.299a 0.052a
Missense(n=29) 0.265a 0.362a 0.033 a 0.015 a 0.164a 0.207a 0.012 a
Frameshift(n=23) 0.001 a 0.070a 0.013 b 0.218a 0.082a 0.140a 0.248b
Deletion(n=1) 1.000b 1.000b 1.000b 1.000b 1.000b 1.000b 1.000b
Silent(n=2) 1.000b 0.067b 1.000b 0.253b 0.183b 0.893b 0.540b
Intronic(n=6) 0.763b 0.118b 0.580b 0.520b 1.000b 1.000b 0.866b

Bold represents having statistical differences.

The “n” in parentheses indicates the number of patients with a positive result for this item.

The superscripts on the right side of the P-value represent different test methods. “a” denotes the Pearson test, and “b” denotes the continuity-corrected test (Yates’ correction).

The results of binary logistic regression analysis.

Project/AnalysisUnivariate analysis Multivariate analysis
P-value OR (95%CI) P-value OR (95%CI)
c.865C>T and Trichophyton <0.001 7.636 (2.258-25.829) 0.038 5.760 (1.098-30.217)
c.865C>T and dematiaceous fungi <0.001 18.543 (4.974-69.125) 0.005 9.653 (2.019-46.153)
c.865C>T and skin 0.998 – – –
c.865C>T and lymph nodes 0.008 4.464 (1.482-13.445) 0.412 –
c.865C>T and invasive infections 0.005 0.171 (0.051-0.581) 0.937 –
c.819_820insG and Trichophyton 0.998 – – –
c.819_820insG and lymph nodes 0.999 – – –
c.883C>T and Candida <0.001 8.585 (2.469-29.844) 0.008 10.421 (1.849-58.748)
Other mutations and Candida 0.018 0.309 (0.117-0.819) 0.131 –
Other mutations and skin 0.005 0.238 (0.088-0.643) 0.053 –
Other mutations and central nervous system 0.039 2.835 (1.054-7.627) 0.644 –
Other mutations and invasive infections 0.031 3.066 (1.109-8.475) 0.550
Nonsense mutation and dematiaceous fungi 0.006 5.100 (1.584-16.422) 0.014 6.212 (1.453-26.556)
Missense mutation and dematiaceous fungi 0.047 0.206 (0.043-0.983) 0.103 –
Missense mutation and skin 0.015 0.303 (0.116-0.792) 0.059 0.304 (0.088-1.048)
Missense mutation and invasive infections 0.014 3.424 (1.286-9.113) 0.147 –
Frameshift mutation and Trichophyton 0.998 – – –
Frameshift mutation and dematiaceous fungi 0.998 – – –

Bold represents having statistical differences in Multivariate analysis.

 Discussion

CARD9, a pivotal downstream component of pattern recognition receptors (PRRs), plays a central role in mediating a cascade of inflammatory responses against invasive fungi, bacteria, viruses, and parasites. Mutations in the CARD9 gene, which lead to reduced expression and functional impairment, are associated with an autosomal recessive primary immunodeficiency disorder. This genetic defect renders affected individuals highly susceptible to microbial infections. The PRRs/Syk/CARD9 signaling pathway, situated downstream of PRRs, is one of the most well-characterized and fundamental signaling cascades in the immune response (Hu et al., 2022). CARD9-related C-type lectin receptors (CLRs) primarily include Dectin-1, Dectin-2, Dectin-3, and Mincle. Upon recognition of carbohydrate agonists, these CLRs recruit the tyrosine kinase Syk following Src kinase-mediated tyrosine phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM)-like motifs (hem-ITAMs) or canonical ITAMs within their cytoplasmic tails (Rogers et al., 2005; Drummond et al., 2011). Syk serves as a pivotal signaling mediator, coupling activated immunoreceptors to downstream pathways in immune cells. Following recruitment, Syk undergoes phosphorylation, triggering the activation of protein kinase Cδ (PKCδ). This, in turn, facilitates the recruitment and phosphorylation of CARD9 at Thr231, initiating downstream signaling cascades (Wang Y. et al., 2020).Animals with a genetic deletion of Card9 are susceptible to challenge with a variety of fungal species, including Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and some rarer dematiaceous fungi (Drummond et al., 2018).

The demographic profile of patients with CARD9-deficiency-associated fungal infections predominantly comprises young and middle-aged individuals. A significant proportion, specifically 57.32% (47 cases) of the patients, experience disease onset during childhood or adolescence. Notably, there are distinct geographical variations in the distribution of CARD9 gene mutations. For instance, the c.820dupG mutation is predominantly observed in East Asia, a finding that aligns with previous research by Tomomasa et al. (Tomomasa et al., 2024). Additionally, our study identified that the c.819-820insG and c.1118G>C mutations are uniquely present in the East Asian region, with 819-820insG being reported exclusively in China. In the case series presented by Lanternier et al. (Lanternier et al., 2013), all 12 patients with the c. 865C>T mutation were from Algeria, Morocco, and Tunisia. Over the past 12 years, 6 additional cases of this mutation have been reported, of which only 3 were from Spain, Turkey and Argentina, and the rest were from the above-mentioned North African countries, indicating that c.865C>T is mainly distributed in North Africa.

Fungal infections associated with CARD9 deficiency exhibit remarkable heterogeneity. The present study documented involvement of 18 distinct anatomical sites and identified 19 different genera of fungal pathogens. Among them, Candida and Trichophyton were the most isolated fungi. Meanwhile, fungal infections in CARD9-deficient patients showed a tendency toward severe invasiveness. According to the classification criteria of Classification and Nomenclature of Fungi, Fungal diseases (Fsbath, 2012), all patients met the criteria for deep infection (involving at least the dermis and subcutaneous tissues). According to the definition of invasive fungal infection (Donnelly et al., 2020), 32.82% of patients had definite invasive infections. Through correlation analysis, we found that the c.883C>T mutation significantly increased the likelihood of Candida infection, consistent with the analysis by Vaezi (Vaezi et al., 2018) and Dantas (Dantas et al., 2024). Moreover, the c.865C>T mutation was associated with an elevated probability of Trichophyton and dematiaceous fungi infection. A previous study (Vaezi et al., 2018) reported an association between c.819-820insG and disseminated phaeohyphomycosis (OR=2.42, 95%CI 1.84–3.2, p<0.001), and we did not find similar results.

The c.883C>T mutation in the CARD9 gene results from the substitution of cytosine (C) with thymine (T) at nucleotide position 883, leading to the premature formation of a stop codon. This reduces the short-term killing ability of CARD9-deficient neutrophils against unopsonized Candida albicans conidia (Gazendam et al., 2014; Corvilain et al., 2018). The c.865C>T mutation, where the cytosine (C) at nucleotide position 865 is replaced by thymine (T), results in a premature stop codon. This mutation inhibits the release of inflammatory cytokines such as IL-6, IL-1β, and IL-17A, potentially serving as the underlying mechanism for Trichophyton infections (Lanternier et al., 2013; Tan et al., 2022). This may explain the different pathogen susceptibilities associated with the two gene mutations. Dematiaceous fungi have been reported to cause subcutaneous and invasive infections, including chromoblastomycosis, phaeohyphomycosis, and mycetoma (McGinnis, 1983). A study investigating the response to pathogenic dematiaceous fungi in Card9-knockout mice found that the inability to control these fungi was associated with a lack of Th17 differentiation and reduced levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-17A in footpad homogenates (Wu et al., 2016). Previous research has not explored the relationship between mutation types and pathogens. We found that nonsense mutations increased the risk of dematiaceous fungi infections, yet the c.883C>T mutation, a relatively frequent nonsense mutation, did not exhibit this association. This discrepancy may be related to epidemiological differences. Although there is limited epidemiological data on dematiaceous fungi in Africa, a study on chromoblastomycosis prevalence, showed that Africa has the second-highest incidence after South America, while the c.883C>T mutation is absent in both regions.

Among the 82 patients included in this study, 13 succumbed to the disease. The majority of these fatal cases were associated with infections of the central nervous system, blood system, and/or viscera. This poor prognosis can be attributed, at least in part, to the reduced effectiveness to antifungal medications, which is a consequence of genetic defects in these patients. The prognosis of CARD9 patients is associated with co-existing mutations in other genes, some of which may exhibit synergistic effects. For example, co-mutations in the DOCK8 gene can lead to severe fungal infections (El Hawary et al., 2022). The genetic heterogeneity of inborn errors of immunity and diagnostic delays in atypical cases lead to significant morbidity and mortality. Establishing a definitive genetic diagnosis is crucial for patient management (Ripen et al., 2021). Among the patients included in this study, 28.05% (23/82) of the patients underwent whole exome sequencing. Only 4 cases were found to have mutations in other genes: P35 (SPAST mutation) (Rieber et al., 2016), P40 (NLRP12 mutation) (Cetinkaya et al., 2018), P52 (STS gene mutation) (Nazarian et al., 2020), and P68 (CD40LG mutation) (Yan et al., 2022). The latter 3 gene mutations are associated with infections, and in these 3 patients, the disease is more severe and the treatment is more difficult. Granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF) exert pleiotropic effects on the innate immune system by enhancing the function of human neutrophils (Lin et al., 2024). While their efficacy has been demonstrated in individual case reports (Gavino et al., 2014; Du et al., 2020), large-scale clinical trials are still lacking. Nevertheless, they represent valuable salvage treatment options for patients who do not respond adequately to conventional antifungal therapy.

In conclusion, CARD9 deficiency should be considered in the differential diagnosis of patients presenting with progressive fungal infections of unknown etiology. Early initiation of antifungal treatment is crucial for improving patient outcomes, and long-term prophylactic treatment and regular follow-up are essential components of comprehensive management strategies.

 Limitations

Our judgment of the patients’ clinical outcomes was subjective and only represented their conditions at that time, which might lead to a certain degree of bias.

There was no subjective classification of anatomical sites, such as the scalp and skin. However, for the integrity of the data, we directly extracted the sites stated in the articles. This might have some impact on the results.

Limited by the low prevalence of CARD9 deficiency, the statistical results may not reflect the true situation, especially for the interpretation of OR values.

This study did not include all CARD9 patients. It only included case reports and case series, and excluded patients without detailed clinical data and those with non-fungal infections.

 Conclusion

In the contemporary landscape of medical research, there has been a burgeoning focus on non-HIV-associated opportunistic infections, which has emerged as a crucial area of investigation due to their increasing prevalence and clinical significance. This study retrospectively analyzed 82 patients with CARD9 deficiency complicated by fungal infections and found significant differences in clinical symptoms, fungal pathogens, and gene mutation sites. It provides potential relationships between gene mutations, pathogens, infection sites, and regional distributions, aiming to enhance the understanding of this disease.

 Author contributions

CT: Methodology, Writing – original draft, Data curation, Software. YL: Software, Writing – original draft, Data curation. JL: Investigation, Writing – review & editing. XL: Supervision, Writing – review & editing.

 Funding

The author(s) declare that no financial support was received for the research and/or publication of this article.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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