Partial DHR Activity Masking X-Linked CGD: An Unusual Adolescent Presentation with Isolated Liver Abscess

Partial DHR Activity Masking X-Linked CGD: An Unusual Adolescent Presentation with Isolated Liver Abscess | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Partial DHR Activity Masking X-Linked CGD: An Unusual Adolescent Presentation with Isolated Liver Abscess Meera Lahlouh, Mohammad Hamdan, Laith Khalaf, Kareem Abdul-Haleem This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8581580/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by a defect in the nicotinamide adenine dinucleotide phosphate oxidase complex, leading to impaired phagocytic respiratory burst and inability to kill microorganisms. It typically presents in early childhood with recurrent, severe infections, with complications like liver abscesses usually occurring in late stages. An initial presentation during adolescence is uncommon and may delay recognition and management. Case Presentation : A previously healthy 14.5-year-old male presented with fever, right upper quadrant abdominal pain, and laboratory findings suggestive of systemic inflammation. Imaging revealed a large liver abscess that recurred after broad-spectrum antimicrobials and percutaneous drainage. Initial immunologic workup was inconclusive; however, oxidative burst testing revealed a reduced neutrophil function. Genetic testing confirmed a hemizygous CYBB gene mutation consistent with X-linked CGD. The patient was started on lifelong antimicrobial prophylaxis, and follow-up into late adolescence showed no further invasive infections. Conclusion CGD can rarely present for the first time in adolescence and initially manifest as a liver abscess. Delayed diagnosis can happen when the classical manifestations are not very obvious; thus, clinicians should maintain a high index of suspicion for CGD in older children, adolescents, and even adult patients with recurrent or resistant liver abscesses. Chronic granulomatous disease Liver abscess Dihydrorhodamine Hematopoietic stem cell transplantation Case report Introduction Chronic granulomatous disease (CGD) is a rare primary immunodeficiency that typically appears within the first 5 years of life and occurs in approximately 1 in 200,000-250,000 live births. It results from an X-linked or autosomal recessive mutation in one of the five subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. These mutations impair the respiratory burst in phagocytes, resulting in an inability to kill certain bacteria and fungi effectively ( 1 – 3 ). Children with CGD often present with recurrent infections, such as suppurative lymphadenitis, staphylococcal skin infections, or pneumonia, and may develop signs of failure to thrive. Prophylactic antimicrobials and antifungals have improved survival, but the only curative option is hematopoietic stem cell transplantation (HSCT), which can correct both infectious and inflammatory complications. We present the case of a male patient who had a liver abscess at the age of 14.5 years as the initial manifestation of CGD ( 1 , 2 ). Case Presentation We present the case of a 21-year-old male, born at term by a cesarean section to non-consanguineous parents, with a free past medical history. At the age of 14.5 years, he developed right upper quadrant abdominal pain accompanied by an undocumented fever, following several days of unsuccessful outpatient antibiotic therapy. Upon admission, laboratory tests revealed a significantly elevated C-reactive protein (207.5 mg/L; normal < 10 mg/L), leukocytosis (13,690/µL; normal 4,600 − 11,000/µL), and anemia (hemoglobin 8.88 g/dL; normal 9.5–14.5 g/dL). Renal function, urinalysis, and stool tests were normal. Abdominal ultrasound revealed a heterogeneous lesion in the liver, and a subsequent CT confirmed a thick-walled abscess in segment VIII measuring 7.9 x 5.6 cm, associated with splenomegaly (17 cm). CT-guided aspiration yielded 30 mL of pus, which grew Staphylococcus aureus upon culture. He was treated initially with piperacillin-tazobactam and metronidazole, then switched to meropenem and metronidazole due to inadequate response. He was discharged 10 days later after a normal abdominal ultrasound. Three months later, he presented with fever and liver abscesses. His laboratory tests revealed leukocytosis (16,000/µL) and an elevated erythrocyte sedimentation rate (70 mm/hour; normal < 50 mm/hour). An immunodeficiency was suspected, so immunological tests were done (Table 1 ), and were all within normal. However, the dihydrorhodamine (DHR) assay revealed an impaired neutrophil oxidative burst, suggesting CGD. Genetic testing revealed a hemizygous mutation in the CYBB gene, confirming the diagnosis of X-linked CGD. Upon diagnosis, he was started on prophylactic trimethoprim-sulfamethoxazole and itraconazole. Family screening revealed that only his mother and older sister were carriers, while his younger sister turned out to be a matched donor for HSCT. Table 1 Immunological tests on the second admission Test Result Normal Range Interpretation Immunoglobulin G (IgG) 1500 mg/dL 700–1600 mg/dL Normal T Cell Count 1458/µL 500–1500/µL Normal B Cell Count 250/µL 100–500/µL Normal Natural Killer Cell Count 140/µL 90–600/µL Normal Over the following year, his condition gradually deteriorated as he developed recurrent liver abscesses, sepsis, lymphadenopathy, and shortness of breath, in addition to suspected endocarditis. CT revealed a multiloculated liver abscess measuring 11 x 9 x 10 cm with necrosis and a left hepatic vein thrombosis. Due to the persistence of symptoms despite a wide range of antimicrobials, he underwent an exploratory laparotomy. Postoperatively, his fever and inflammatory markers gradually improved. During follow-up, no new liver abscesses were detected; however, atrophy of the left hepatic lobe was noted, along with a residual calcified mass measuring 7 x 4 x 4.3 cm. Although HSCT was recommended as soon as possible, logistical barriers prevented it. Despite this, the patient remained stable over the next two years, with appropriate growth, a body mass index of 26, and preserved pulmonary function. By the latest follow-up, he is still on prophylactic therapy while awaiting the availability of a transplantation. Discussion CGD is a rare primary immunodeficiency, affecting approximately 1 in 200,000-250,000 live births, with higher prevalence among North African and Arab populations due to consanguineous marriage ( 3 , 4 ). It results from mutations in one of the five subunits of the NADPH oxidase complex, which produces reactive oxygen species as a first-line defense against pathogens ( 4 , 5 ). Mutated NADPH oxidase complex impairs the phagocytic respiratory burst, increasing susceptibility to severe bacterial and fungal infections, most commonly by Staphylococcus aureus and Aspergillus spp. These infections typically manifest in early childhood, with most cases diagnosed before the age of 5 years (median age 2.7-3 years) ( 3 – 5 ), unlike our patient, who had his first manifestation of CGD at the age of 14.5 years. Approximately 65% of CGD cases are caused by an X-linked mutation in the CYBB gene, which encodes the 91-kd membrane glycoprotein of phagocyte oxidase (gp91-phox). Other glycoproteins can be affected by autosomal recessive mutations, but they usually present later and are less severe than the X-linked form ( 3 , 5 – 7 ). Late detection may result from residual activity of the NADPH oxidase complex, particularly in autosomal recessive forms, leading to misdiagnosis or a better prognosis ( 3 – 7 ). Patients most commonly present with pyogenic infections involving the lungs, skin, lymph nodes, and liver, with recurrent pneumonia being the most common worldwide. Another hallmark of CGD is the formation of non-caseating sterile granulomas, which mostly involve the bladder, stomach, and colon, but can involve any part of the gastrointestinal tract, with the esophagus being the least commonly affected. These granulomas can present as inflammatory bowel disease or obstruction of hollow viscera ( 3 – 5 , 8 ). 30–50% of patients develop liver abscesses, most commonly caused by Staphylococcus aureus. They present with abdominal pain, fever, weight loss, and elevated inflammatory markers. Liver involvement may be associated with nodular regenerative hyperplasia, portal hypertension and venopathy, and splenomegaly, which is considered a poor prognostic factor, as it can cause thrombocytopenia. Typically, liver abscesses are seen in later stages of CGD rather than the first manifestation of the disease ( 3 , 4 ). Our patient presented with a liver abscess as the first manifestation of CGD at the age of 15 years and had a free past medical history, distinguishing him from previously reported cases. The first report described a 12-year-old male who presented with a liver abscess but had a suspicious pneumonia and parapneumonic effusion one year before ( 6 ). The second report described a 37-year-old male who presented with a liver abscess but had a previous abscess and multiple childhood infections and hospital admissions ( 4 ). Delayed CGD has also been reported in a 52-year-old male who first presented with Aspergillus pneumonia; this patient had the autosomal recessive form, often associated with milder and later presentation due to residual NADPH oxidase activity ( 9 ). In contrast, our patient had an X-linked CYBB mutation, usually associated with more severe early-onset disease ( 3 , 5 – 7 ). The DHR assay remains the diagnostic method of choice. It uses flow cytometry to quantify rhodamine 123 oxidation by NADPH in phagocytes. This assay distinguishes CGD forms, provides prognostic information, and even detects carriers. Genetic testing is required to confirm the diagnosis following abnormal DHR findings ( 3 , 4 ). In our patient, genetic testing revealed a missense mutation in the CYBB gene. The DHR assay showed 7.5% oxidation without stimulation and 48.1% with phorbol myristate acetate stimulation, compared to normal values of 3.8% and 95%, respectively. These results showed a higher-than-normal baseline and lower-than-normal stimulated response, suggesting residual NADPH oxidase activity, which is uncommon in X-linked CGD ( 10 ). Management focuses on preventing infections through lifelong prophylactic trimethoprim-sulfamethoxazole and itraconazole. Interferon-gamma may be used to stimulate immunity; however, hematopoietic stem cell transplantation remains the only curative therapy until now. These methods have successfully increased the median age of death among CGD patients over the last few decades ( 3 – 5 ). Conclusion CGD is a rare primary immunodeficiency that usually presents with severe bacterial and fungal infections in early childhood, leading to diagnosis before the age of 5 years. Residual NADPH oxidase complex activity may result in a delayed presentation, especially in the autosomal recessive form. We recommend suspecting CGD even in adolescent and adult patients. Advanced manifestations such as liver abscess can be the first sign of disease, even in the absence of prior infections. Abbreviations CGD: chronic granulomatous disease NADPH: nicotinamide adenine dinucleotide phosphate HSCT: hematopoietic stem cell transplantation DHR: dihydrorhodamine Declarations Ethics approval and consent to participate Informed consent was obtained from the patient for both participation and publication of this report. Consent for publication Informed consent was obtained from the patient for both participation and publication of this report. Data availability Not applicable. This manuscript does not report data generation or analysis. Competing interests The authors declare that they have no competing interests. Funding This article received no funding. Authors' contributions All authors contributed to manuscript writing and approved the final version. Acknowledgments Not applicable. Clinical trial number Not applicable. References Rider NL, Jameson MB, Creech CB. Chronic Granulomatous Disease: Epidemiology, Pathophysiology, and Genetic Basis of Disease. J Pediatr Infect Dis Soc. 2018 May;7(Suppl 1):S2–5. Arnold DE, Heimall JR. A Review of Chronic Granulomatous Disease. Adv Ther. 2017 Dec 1;34(12):2543–57. Justiz-Vaillant AA, Williams-Persad AFA, Arozarena-Fundora R, Gopaul D, Soodeen S, Asin-Milan O, et al. Chronic Granulomatous Disease (CGD): Commonly Associated Pathogens, Diagnosis and Treatment. Microorganisms [Internet]. 2023 Sept 5 [cited 2025 Dec 11];11(9). Available from: https://www.mdpi.com/2076-2607/11/9/2233 Charisi K, Terzaki M, Bangeas A, Taparkou A, Papadimitriou E, Karypidou E, et al. Liver Abscess: Think Outside the Box. Cureus. 17(6):e86755. Barkai T, Somech R, Broides A, Gavrieli R, Wolach B, Marcus N, et al. Late diagnosis of chronic granulomatous disease. Clin Exp Immunol. 2020 Sept;201(3):297–305. Al Ghadeer HA, Busaleh FN, Al Habeeb JA, Alaithan RM, Almutahhar AE, Bin Abd MM, et al. Liver Abscesses as a Sign of Chronic Granulomatous Disease in Adolescent. Cureus. 13(8):e17467. Schapiro BL, Newburger PE, Klempner MS, Dinauer MC. Chronic Granulomatous Disease Presenting in a 69-Year-Old Man. N Engl J Med. 1991 Dec 19;325(25):1786–90. Leiding JW, Holland SM. Chronic Granulomatous Disease. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2025 Dec 11]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK99496/ Marois L, Drouin D, Leduc C, Fernandez I, Manganas H, Gosse G, et al. Chronic granulomatous disease presenting at age 52 with fulminant mulch pneumonitis. J Allergy Clin Immunol Glob. 2022 Nov;1(4):322–4. O’Donovan CJ, Tan LT, Abidin MAZ, Roderick MR, Grammatikos A, Bernatoniene J. Diagnosis of Chronic Granulomatous Disease: Strengths and Challenges in the Genomic Era. J Clin Med. 2024 July 29;13(15):4435. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 17 Feb, 2026 Reviews received at journal 12 Feb, 2026 Reviewers agreed at journal 11 Feb, 2026 Reviews received at journal 09 Feb, 2026 Reviewers agreed at journal 09 Feb, 2026 Reviewers invited by journal 08 Feb, 2026 Editor invited by journal 15 Jan, 2026 Editor assigned by journal 14 Jan, 2026 Submission checks completed at journal 14 Jan, 2026 First submitted to journal 12 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8581580","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":589491286,"identity":"ec204beb-178b-4eaf-96cd-5bc6af4b0265","order_by":0,"name":"Meera Lahlouh","email":"","orcid":"","institution":"An-Najah National University","correspondingAuthor":false,"prefix":"","firstName":"Meera","middleName":"","lastName":"Lahlouh","suffix":""},{"id":589491288,"identity":"2177901f-0387-40de-a7e7-e8f4bd2263ae","order_by":1,"name":"Mohammad Hamdan","email":"","orcid":"","institution":"Palestinian Governmental Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"","lastName":"Hamdan","suffix":""},{"id":589491289,"identity":"c691488f-48e0-4224-9a5e-620729c3c527","order_by":2,"name":"Laith Khalaf","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIie3PsUvDQBTH8ReEm2LB7ZUW+y9cEU6HmPwhLi8EkiWCY4cOkcK56C44+Bc4uDhfCWQKZg24XHaHjhkcvHSVpO1W8L7j8fvwOACb7QhDBEeBdwUMXEcT98ybc692EFAQIzDmnnC9iDuS7UeAuexMl/n2dZCMX1ZatYSz0eypgFBW/ttDbq4svZs+MpkWfP1IOJdsFOtQfkUfZWhIEd9mPeQciavTFh3J3EveEaEMcbJ8gCSb9Q9hYIjAUH5GomqGyQRTnrtkxh2hUvmi3nFl/Jze5VPCSLL0gtMiIlGbKzTwF6yT9+abvOvXVTlvWu4HokoavVl6veRP4XZJ+867gkPGNpvN9j/6BZniZDRNf/ODAAAAAElFTkSuQmCC","orcid":"","institution":"An-Najah National University","correspondingAuthor":true,"prefix":"","firstName":"Laith","middleName":"","lastName":"Khalaf","suffix":""},{"id":589491291,"identity":"284f9c5e-1447-4e1c-9f3a-b64e4716a6c3","order_by":3,"name":"Kareem Abdul-Haleem","email":"","orcid":"","institution":"An-Najah National University","correspondingAuthor":false,"prefix":"","firstName":"Kareem","middleName":"","lastName":"Abdul-Haleem","suffix":""}],"badges":[],"createdAt":"2026-01-12 12:09:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8581580/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8581580/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102746590,"identity":"949c6775-9290-418a-bf91-24a9e7dc594f","added_by":"auto","created_at":"2026-02-16 08:58:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":303224,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8581580/v1/ef07e6fb-41d5-4907-9ba3-726d6f85fdb6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Partial DHR Activity Masking X-Linked CGD: An Unusual Adolescent Presentation with Isolated Liver Abscess","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic granulomatous disease (CGD) is a rare primary immunodeficiency that typically appears within the first 5 years of life and occurs in approximately 1 in 200,000-250,000 live births. It results from an X-linked or autosomal recessive mutation in one of the five subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. These mutations impair the respiratory burst in phagocytes, resulting in an inability to kill certain bacteria and fungi effectively (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eChildren with CGD often present with recurrent infections, such as suppurative lymphadenitis, staphylococcal skin infections, or pneumonia, and may develop signs of failure to thrive. Prophylactic antimicrobials and antifungals have improved survival, but the only curative option is hematopoietic stem cell transplantation (HSCT), which can correct both infectious and inflammatory complications. We present the case of a male patient who had a liver abscess at the age of 14.5 years as the initial manifestation of CGD (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eWe present the case of a 21-year-old male, born at term by a cesarean section to non-consanguineous parents, with a free past medical history. At the age of 14.5 years, he developed right upper quadrant abdominal pain accompanied by an undocumented fever, following several days of unsuccessful outpatient antibiotic therapy. Upon admission, laboratory tests revealed a significantly elevated C-reactive protein (207.5 mg/L; normal\u0026thinsp;\u0026lt;\u0026thinsp;10 mg/L), leukocytosis (13,690/\u0026micro;L; normal 4,600\u0026thinsp;\u0026minus;\u0026thinsp;11,000/\u0026micro;L), and anemia (hemoglobin 8.88 g/dL; normal 9.5\u0026ndash;14.5 g/dL). Renal function, urinalysis, and stool tests were normal.\u003c/p\u003e \u003cp\u003eAbdominal ultrasound revealed a heterogeneous lesion in the liver, and a subsequent CT confirmed a thick-walled abscess in segment VIII measuring 7.9 x 5.6 cm, associated with splenomegaly (17 cm). CT-guided aspiration yielded 30 mL of pus, which grew \u003cem\u003eStaphylococcus aureus\u003c/em\u003e upon culture. He was treated initially with piperacillin-tazobactam and metronidazole, then switched to meropenem and metronidazole due to inadequate response. He was discharged 10 days later after a normal abdominal ultrasound.\u003c/p\u003e \u003cp\u003eThree months later, he presented with fever and liver abscesses. His laboratory tests revealed leukocytosis (16,000/\u0026micro;L) and an elevated erythrocyte sedimentation rate (70 mm/hour; normal\u0026thinsp;\u0026lt;\u0026thinsp;50 mm/hour). An immunodeficiency was suspected, so immunological tests were done (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), and were all within normal. However, the dihydrorhodamine (DHR) assay revealed an impaired neutrophil oxidative burst, suggesting CGD. Genetic testing revealed a hemizygous mutation in the CYBB gene, confirming the diagnosis of X-linked CGD. Upon diagnosis, he was started on prophylactic trimethoprim-sulfamethoxazole and itraconazole. Family screening revealed that only his mother and older sister were carriers, while his younger sister turned out to be a matched donor for HSCT.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eImmunological tests on the second admission\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResult\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNormal Range\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunoglobulin G (IgG)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1500 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e700\u0026ndash;1600 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT Cell Count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1458/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e500\u0026ndash;1500/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB Cell Count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e250/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100\u0026ndash;500/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNatural Killer Cell Count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e140/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90\u0026ndash;600/\u0026micro;L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOver the following year, his condition gradually deteriorated as he developed recurrent liver abscesses, sepsis, lymphadenopathy, and shortness of breath, in addition to suspected endocarditis. CT revealed a multiloculated liver abscess measuring 11 x 9 x 10 cm with necrosis and a left hepatic vein thrombosis. Due to the persistence of symptoms despite a wide range of antimicrobials, he underwent an exploratory laparotomy. Postoperatively, his fever and inflammatory markers gradually improved.\u003c/p\u003e \u003cp\u003eDuring follow-up, no new liver abscesses were detected; however, atrophy of the left hepatic lobe was noted, along with a residual calcified mass measuring 7 x 4 x 4.3 cm. Although HSCT was recommended as soon as possible, logistical barriers prevented it. Despite this, the patient remained stable over the next two years, with appropriate growth, a body mass index of 26, and preserved pulmonary function. By the latest follow-up, he is still on prophylactic therapy while awaiting the availability of a transplantation.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCGD is a rare primary immunodeficiency, affecting approximately 1 in 200,000-250,000 live births, with higher prevalence among North African and Arab populations due to consanguineous marriage (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). It results from mutations in one of the five subunits of the NADPH oxidase complex, which produces reactive oxygen species as a first-line defense against pathogens (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Mutated NADPH oxidase complex impairs the phagocytic respiratory burst, increasing susceptibility to severe bacterial and fungal infections, most commonly by \u003cem\u003eStaphylococcus aureus\u003c/em\u003e and \u003cem\u003eAspergillus\u003c/em\u003e spp. These infections typically manifest in early childhood, with most cases diagnosed before the age of 5 years (median age 2.7-3 years) (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), unlike our patient, who had his first manifestation of CGD at the age of 14.5 years.\u003c/p\u003e \u003cp\u003eApproximately 65% of CGD cases are caused by an X-linked mutation in the CYBB gene, which encodes the 91-kd membrane glycoprotein of phagocyte oxidase (gp91-phox). Other glycoproteins can be affected by autosomal recessive mutations, but they usually present later and are less severe than the X-linked form (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Late detection may result from residual activity of the NADPH oxidase complex, particularly in autosomal recessive forms, leading to misdiagnosis or a better prognosis (\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatients most commonly present with pyogenic infections involving the lungs, skin, lymph nodes, and liver, with recurrent pneumonia being the most common worldwide. Another hallmark of CGD is the formation of non-caseating sterile granulomas, which mostly involve the bladder, stomach, and colon, but can involve any part of the gastrointestinal tract, with the esophagus being the least commonly affected. These granulomas can present as inflammatory bowel disease or obstruction of hollow viscera (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e30\u0026ndash;50% of patients develop liver abscesses, most commonly caused by Staphylococcus aureus. They present with abdominal pain, fever, weight loss, and elevated inflammatory markers. Liver involvement may be associated with nodular regenerative hyperplasia, portal hypertension and venopathy, and splenomegaly, which is considered a poor prognostic factor, as it can cause thrombocytopenia. Typically, liver abscesses are seen in later stages of CGD rather than the first manifestation of the disease (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur patient presented with a liver abscess as the first manifestation of CGD at the age of 15 years and had a free past medical history, distinguishing him from previously reported cases. The first report described a 12-year-old male who presented with a liver abscess but had a suspicious pneumonia and parapneumonic effusion one year before (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The second report described a 37-year-old male who presented with a liver abscess but had a previous abscess and multiple childhood infections and hospital admissions (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Delayed CGD has also been reported in a 52-year-old male who first presented with Aspergillus pneumonia; this patient had the autosomal recessive form, often associated with milder and later presentation due to residual NADPH oxidase activity (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In contrast, our patient had an X-linked CYBB mutation, usually associated with more severe early-onset disease (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe DHR assay remains the diagnostic method of choice. It uses flow cytometry to quantify rhodamine 123 oxidation by NADPH in phagocytes. This assay distinguishes CGD forms, provides prognostic information, and even detects carriers. Genetic testing is required to confirm the diagnosis following abnormal DHR findings (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In our patient, genetic testing revealed a missense mutation in the CYBB gene. The DHR assay showed 7.5% oxidation without stimulation and 48.1% with phorbol myristate acetate stimulation, compared to normal values of 3.8% and 95%, respectively. These results showed a higher-than-normal baseline and lower-than-normal stimulated response, suggesting residual NADPH oxidase activity, which is uncommon in X-linked CGD (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eManagement focuses on preventing infections through lifelong prophylactic trimethoprim-sulfamethoxazole and itraconazole. Interferon-gamma may be used to stimulate immunity; however, hematopoietic stem cell transplantation remains the only curative therapy until now. These methods have successfully increased the median age of death among CGD patients over the last few decades (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCGD is a rare primary immunodeficiency that usually presents with severe bacterial and fungal infections in early childhood, leading to diagnosis before the age of 5 years. Residual NADPH oxidase complex activity may result in a delayed presentation, especially in the autosomal recessive form. We recommend suspecting CGD even in adolescent and adult patients. Advanced manifestations such as liver abscess can be the first sign of disease, even in the absence of prior infections.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eCGD: chronic granulomatous disease\u003c/li\u003e\n \u003cli\u003eNADPH: nicotinamide adenine dinucleotide phosphate\u003c/li\u003e\n \u003cli\u003eHSCT: hematopoietic stem cell transplantation\u003c/li\u003e\n \u003cli\u003eDHR: dihydrorhodamine\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient for both participation and publication of this report.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient for both participation and publication of this report.\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eNot applicable. This manuscript does not report data generation or analysis.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis article received no funding.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eAll authors contributed to manuscript writing and approved the final version.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eClinical trial number\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRider NL, Jameson MB, Creech CB. Chronic Granulomatous Disease: Epidemiology, Pathophysiology, and Genetic Basis of Disease. J Pediatr Infect Dis Soc. 2018 May;7(Suppl 1):S2\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eArnold DE, Heimall JR. A Review of Chronic Granulomatous Disease. Adv Ther. 2017 Dec 1;34(12):2543\u0026ndash;57. \u003c/li\u003e\n\u003cli\u003eJustiz-Vaillant AA, Williams-Persad AFA, Arozarena-Fundora R, Gopaul D, Soodeen S, Asin-Milan O, et al. Chronic Granulomatous Disease (CGD): Commonly Associated Pathogens, Diagnosis and Treatment. Microorganisms [Internet]. 2023 Sept 5 [cited 2025 Dec 11];11(9). Available from: https://www.mdpi.com/2076-2607/11/9/2233\u003c/li\u003e\n\u003cli\u003eCharisi K, Terzaki M, Bangeas A, Taparkou A, Papadimitriou E, Karypidou E, et al. Liver Abscess: Think Outside the Box. Cureus. 17(6):e86755. \u003c/li\u003e\n\u003cli\u003eBarkai T, Somech R, Broides A, Gavrieli R, Wolach B, Marcus N, et al. Late diagnosis of chronic granulomatous disease. Clin Exp Immunol. 2020 Sept;201(3):297\u0026ndash;305. \u003c/li\u003e\n\u003cli\u003eAl Ghadeer HA, Busaleh FN, Al Habeeb JA, Alaithan RM, Almutahhar AE, Bin Abd MM, et al. Liver Abscesses as a Sign of Chronic Granulomatous Disease in Adolescent. Cureus. 13(8):e17467. \u003c/li\u003e\n\u003cli\u003eSchapiro BL, Newburger PE, Klempner MS, Dinauer MC. Chronic Granulomatous Disease Presenting in a 69-Year-Old Man. N Engl J Med. 1991 Dec 19;325(25):1786\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eLeiding JW, Holland SM. Chronic Granulomatous Disease. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews\u0026reg; [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2025 Dec 11]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK99496/\u003c/li\u003e\n\u003cli\u003eMarois L, Drouin D, Leduc C, Fernandez I, Manganas H, Gosse G, et al. Chronic granulomatous disease presenting at age 52 with fulminant mulch pneumonitis. J Allergy Clin Immunol Glob. 2022 Nov;1(4):322\u0026ndash;4. \u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Donovan CJ, Tan LT, Abidin MAZ, Roderick MR, Grammatikos A, Bernatoniene J. Diagnosis of Chronic Granulomatous Disease: Strengths and Challenges in the Genomic Era. J Clin Med. 2024 July 29;13(15):4435. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Chronic granulomatous disease, Liver abscess, Dihydrorhodamine, Hematopoietic stem cell transplantation, Case report","lastPublishedDoi":"10.21203/rs.3.rs-8581580/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8581580/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eChronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by a defect in the nicotinamide adenine dinucleotide phosphate oxidase complex, leading to impaired phagocytic respiratory burst and inability to kill microorganisms. It typically presents in early childhood with recurrent, severe infections, with complications like liver abscesses usually occurring in late stages. An initial presentation during adolescence is uncommon and may delay recognition and management.\u003c/p\u003e\u003ch2\u003eCase Presentation\u003c/h2\u003e \u003cp\u003e: A previously healthy 14.5-year-old male presented with fever, right upper quadrant abdominal pain, and laboratory findings suggestive of systemic inflammation. Imaging revealed a large liver abscess that recurred after broad-spectrum antimicrobials and percutaneous drainage. Initial immunologic workup was inconclusive; however, oxidative burst testing revealed a reduced neutrophil function. Genetic testing confirmed a hemizygous CYBB gene mutation consistent with X-linked CGD. The patient was started on lifelong antimicrobial prophylaxis, and follow-up into late adolescence showed no further invasive infections.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eCGD can rarely present for the first time in adolescence and initially manifest as a liver abscess. Delayed diagnosis can happen when the classical manifestations are not very obvious; thus, clinicians should maintain a high index of suspicion for CGD in older children, adolescents, and even adult patients with recurrent or resistant liver abscesses.\u003c/p\u003e","manuscriptTitle":"Partial DHR Activity Masking X-Linked CGD: An Unusual Adolescent Presentation with Isolated Liver Abscess","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-12 18:35:58","doi":"10.21203/rs.3.rs-8581580/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"114321106754213265312935854788522985374","date":"2026-02-17T14:03:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-12T05:05:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"75596697304549735404963197226256094180","date":"2026-02-11T09:18:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-09T14:13:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"20672800435839814853780188045669534186","date":"2026-02-09T13:51:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-09T04:33:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-16T02:30:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-14T07:41:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-14T07:38:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2026-01-12T12:02:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bb098b58-7420-41b3-a18a-8bb7dda42e4a","owner":[],"postedDate":"February 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-12T18:35:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-12 18:35:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8581580","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8581580","identity":"rs-8581580","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}