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Chronic Granulomatous Disease Presenting as Aseptic Ascites in a 2-Year-Old Child

Chronic Granulomatous Disease Presenting as Aseptic Ascites in a 2-Year-Old Child Hindawi Publishing Corporation Case Reports in Immunology Volume 2013, Article ID 927897, 5 pages http://dx.doi.org/10.1155/2013/927897 Case Report Chronic Granulomatous Disease Presenting as Aseptic Ascites in a 2-Year-Old Child 1 2 3 4 5 J. F. Moreau, John A. Ozolek, P. Ling Lin, Todd D. Green, Elaine A. Cassidy, 6 7 Veena L. Venkat, and Andrew R. Buchert School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA Division of Pathology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Division of Infectious Disease, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Division of Pulmonary Medicine, Allergy and Immunology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Division of Rheumatology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Division of Gastroenterology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA eTh Paul C. Gaffney Diagnostic Referral Service, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Correspondence should be addressed to Andrew R. Buchert; andrew.buchert@chp.edu Received 7 December 2012; Accepted 27 December 2012 Academic Editors: N. Kutukculer, C. Pignata, A. Plebani, and A. Vojdani Copyright © 2013 J. F. Moreau et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome that results from abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function. This defect leads to recurrent catalase-positive bacterial and fungal infections as well as associated granuloma formation. We review the case of a 2-year-old boy who presented with ascites and fever of an unknown origin as manifestations of CGD. Cultures were negative for infection throughout his course, and CGD was suspected aer ft identification of granulomas on peritoneal biopsy. Genetic testing revealed a novel mutation in the CYBB gene underlying his condition. This paper highlights the importance of considering CGD in the differential diagnosis of fever of unknown origin and ascites in children. 1. Introduction that occurs within 4 years of diagnosis (43%) [2]. Other pre- senting infections include osteomyelitis, liver and perirectal Chronic granulomatous disease (CGD) results from the abscesses, enteritis, and septicemia [1]. CGD can, in very rare inability of neutrophils to complete the rst fi step of the circumstances, present with ascites [3]. respiratory burst pathway, generation of superoxide, with The incidence of CGD is estimated to be between the downstream consequence of impaired microbe killing. 1/200,000 and 1/250,000 US births [2]. Most affected indi- CGD leads to recurrent and potentially lethal infections. viduals are male because approximately 70% of mutations Pneumonia is the most common infection before diagnosis are X-linked recessive; the remaining 30% of cases are (47%) [1] and occurs in the majority (79%) of patients within autosomal recessive [1, 2, 4]. In normal individuals, inflam- four years of diagnosis [2]. Lymphadenitis is the second matory stimuli prompt nicotinamide adenine dinucleotide most common infection before diagnosis (45%) [1], and phosphate (NADPH) oxidase (a lysosomal enzyme encoded subcutaneous abscess is the second most common infection on chromosome 22) to produce superoxide. Superoxide is 2 Case Reports in Immunology converted to hydrogen peroxide via superoxide dismutase Lyme disease, toxoplasmosis, Bartonella, cytomegalovirus, andthentohypochlorousacid(by myeloperoxidase),which and tuberculosis were also considered. Subsequent testing is lethal to bacteria [5]. Individuals with CGD are able to excluded these infectious entities. utilize hydrogen peroxide made by microbes and convert it to After a few days, he defervesced and was discharged home hypochlorous acid to preserve microbe killing, yet catalase- with presumptive diagnosis of a likely, yet to be diagnosed, positive bacteria can prevent this step by degrading the rheumatological disease. One month later, he developed per- hydrogen peroxide. us, Th catalase-positive organisms such sistent fever and abdominal distension. Exam was now sig- as Staphylococcus aureus are the most common microbial nificant for increased abdominal girth, and a u fl id wave was sources of infection; other common pathogenic organisms present on physical examination. Laboratory studies revealed in patients with CGD are Burkholderia cepacia, Nocardia, an increased platelet count (457× 10 /L) and ESR (74 mm/hr) Serratia,and Klebsiella [2, 6]. Approximately 70% of CGD as well as decreased ferritin (79.2 ng/mL) and Hgb (9.9 g/dL). cases are associated with mutations in the CYBB gene on the His albumin also remained low, prompting testing for preal- X chromosome, but well over 300 different CYBB mutations bumin (low at 5.6 mg/dL), proteinuria (negative), and protein have been reported in association with the disease [7]. In this losing enteropathy (alpha-1-antitrypsin normal (<20)). An paper, we describeanunusual case of CGDinachildwitha abdominal CT scan showed contour irregularity of the novel mutation in exon 13 of the CYBB gene who presented colon, ascites, and diffuse peritoneal enhancement with with an isolated lymphadenitis and months later developed fat stranding consistent with peritonitis. Paracentesis was ascites and culture-negative, granulomatous peritonitis. done, and cytological evaluation demonstrated purulent u fl id with large numbers of neutrophils and macrophages butnomalignant cells. Bacterialand fungal cultures were sterile. The serum-to-ascites albumin gradient was 1 g/L, 2. Case Report likely excluding portal hypertension as an etiology of the The patient is a 2-year-old male born to a G1P1 mother ascites. Gastrointestinal evaluation included esophagogastro- who had an uncomplicated pregnancy and delivery. His only duodenoscopy and colonoscopy with biopsies, endomysial signica fi nt past medical history was an isolated infection one antibody,amylase,and lipase.Duodenal,terminalileal,and and a half years earlier. His parents noticed a swollen area colonic biopsies were unremarkable and without villous on his neck near his left ear and took him to our tertiary abnormalities, inflammatory lymphoid cells, or accumulation care children’s hospital for evaluation. On admission, he was of pigmented macrophages; the other studies were likewise ∘ 9 febrile to 39.3 C and had a leukocytosis of 20 × 10 /L. A normal.Bonemarrowbiopsywasunremarkable,andatagged diagnosis of lymphadenitis was made. A culture of the uid fl WBC scan demonstrated no specific abnormal foci of uptake. drained from the abscess grew methicillin-sensitive S. aureus, His abdomen remained distended, but the girth was stable. butthe blood culturewas negative.Hewas discharged home He defervesced on ampicillin/sulbactam and metronidazole on amoxicillin/clavulanate. eTh neck swelling returned after and was discharged home to complete an empiric course of a few days despite oral antibiotics, prompting his parents antibiotics for peritonitis. to bring him back to the hospital. The abscess was drained One week later, he again developed persistent fever and for the second time, and he was administered intravenous increasing abdominal distension and pain, resulting in his ampicillin/sulbactam. With subsidence of the swelling, the refusal to walk. An exploratory laparoscopy revealed massive patient was discharged home to complete a 10-day course of ascites and an inflamed and friable peritoneum studded antibiotics and had no recurrence of the abscess. with yellow and white nodules. The ascitic uid fl was sent In September 2011, he was admitted with nearly one for culture, and biopsies of the peritoneum were taken. month of daily fevers up to 39.4 C. His only other symptoms The ascitic uid fl had 1500 WBCs but was sterile. Pathology were intermittent dysuria and slightly loose stools at normal of the peritoneal biopsies revealed acute and organizing frequency (1-2 times daily). Family history of immunological, peritonitis with granulomatous features but no evidence of hematological, and oncological diseases was negative. There fungal, acid-fast, or bacterial microorganisms (Figure 1). The was no recent travel. Physical exam was within normal granulomatous nature of the peritonitis prompted evaluation limits except for poor weight gain (decline from 36th to 7th for CGD. A dihydrorhodamine (DHR) test was performed percentile from 12 months of age to admission (28 months)). to assess oxidase burst capability and resulted in negligible Abnormal laboratory values included albumin 2.8 g/dL fluorescence, consistent with CGD. Genetic testing revealed (3.8–5.4 g/dL), alkaline phosphatase 509 IU/L (<290 IU/L), hemizygosity for the c.1683dupG mutation in exon 13 of the C-reactive protein (CRP) 10.69 mg/dL (0.08–1.2 mg/dL), CYBB gene. erythrocyte sedimentation rate (ESR) 131 mm/hr (0– 20 mm/hr), ferritin 178.1 ng/mL (10–60 ng/mL), hemoglobin (Hgb) 10.7 g/dL (11.5–13.5 g/dL), hematocrit 30.5% (34.0– 3. Discussion 40.0%), lactate dehydrogenase 258 IU/L (<171 IU/L), platelets 9 9 399 × 10 /L (156–369 × 10 /L), and neutrophils 57% (12– CGD was first described in 1957 independently by Berendes 34%). All other laboratory values were within normal et al. [8] and by Landing and Shirkey [9]asalethal limits. eTh differential diagnoses included Kawasaki disease, disease in males associated with increased susceptibility hematological malignancy, early juvenile idiopathic arthritis to infection and pigment-containing macrophages in the or other rheumatologic process, and intestinal infection. visceral organs. eTh pigment forms as macrophages clear Case Reports in Immunology 3 (a) (b) (c) Figure 1: (a) Biopsy of peritoneal nodules demonstrated a cellular and organizing peritonitis including neutrophils, mesothelial cells, and abundant macrophages some with epithelioid features (HE, 200x). Focal areas had relatively well-organized granulomas (b) with macrophages that did not express the activated macrophage marker CD163 (c) ((b); HE, 200x, (c); CD163, 200x). neutrophils that have undergone apoptosis, with subsequent 20% and 5%, resp.) [1, 2, 4, 13]. Rac2 (on chromosome 22) cytoplasmic accumulation of ceroid pigment, hence their andp40phox (NCF4geneonchromosome22) arethe other golden or orange-brown color by light microscopy [10]. In the 2 NADPH oxidase subunits, and mutations have thus far not 1960s and 1970s, defective NADPH oxidase was found to be been associated with CGD. the cause of CGD, leading to development of the nitroblue We describe a child with CGD who presents with a rare tetrazolium (NBT) test for diagnosis [11, 12]. A few decades constellation of fever of an unknown origin, ascites, and later, the DHR was developed as more quantitative measure culture-negative peritonitis. To our knowledge, this is the of oxidative burst, and it is now the preferred test for CGD rfi st reported case of CGD associated with a c.1683dupG [12]. Since then, over 400 mutations coding for the NADPH mutation in the CYBB gene [14, 15]. The c.1683dupG mutation oxidaseenzymehavebeendiscovered, andgenetic testingfor in the CYBB gene causes a frameshift mutation that results CGD has become available. in formation of a stop codon and thus loss of normal protein function. Ascites has rarely been reported as a presenting sign Cases of CGD have been associated with defects in of chronic granulomatous disease, and, in all of the previously genes encoding 4 of the 6 NADPH oxidase subunits, named reported cases, bacterial cultures were positive [3, 16, 17]. Our with reference to their molecular mass (kd) and “phox” patient did have nonspecific findings that are oen ft present for phagocyte oxidase. Flavocytochrome b558 is the redox in patients with CGD (fever, microcytic anemia, failure to center of NADPH oxidase and is composed of gp91phox thrive). Whilehehad asomewhatcomplicated lymphadenitis and p22phox. Defects in the X-linked gene encoding gp-91 in the past, he lacked other infections and the chronicity (CYBB) account for about 70% of known mutations causing typical of patients with CGD. CGD, and autosomal recessive p22phox mutations (CYBA gene on chromosome 16) account for an additional 5%. P47- This paper highlights the importance of considering phox (NCF1geneonchromosome7)and p67phox(NCF2 chronic granulomatous disease in the differential diagnosis of gene on chromosome 1) are both regulatory proteins that have fever of unknown origin and ascites. With a broad differential also been associated with autosomal recessive defects (about diagnosis and little direct evidence of CGD before peritoneal 4 Case Reports in Immunology biopsy, our patient reflects the challenge of making this with chronic granulomatous disease. He edited and approved diagnosis. The previously unreported mutation discovered the n fi al paper as submitted. in this patient may have been responsible for his unique clinical presentation. Past research has found that specific References genetic polymorphisms are associated with development of gastrointestinal inflammation and rheumatologic disorders [1] B. Martire, R. Rondelli, A. Soresina et al., “Clinical features, in CGD patients [18]. Otherworkhas shownthatthe long-term follow-up and outcome of a large cohort of patients with chronic granulomatous disease: an Italian multicenter quantity of residual neutrophil reactive oxygen intermediates study,” Clinical Immunology, vol. 126, no. 2, pp. 155–164, 2008. produced in CGD patients is mutation related and correlates [2] J. A. Winkelstein, M. C. Marino, R. B. Johnston et al., “Chronic with clinical outcomes [19]. In this context, knowing patient granulomatous disease: report on a national registry of 368 genotype may enable clinicians to provide improved care and patients,” Medicine,vol.79, no.3,pp. 155–169, 2000. is an area that we feel deserves further investigation. [3] M.Castro, L. Balducci,C.Ciueff tti, V. Lucidi,A.Torre,and S. Bella, “Ascites as an unusual manifestation of chronic granu- lomatous disease in childhood,” Pediatria Medica e Chirurgica, Abbreviations vol. 14,no. 3, pp.317–319,1992. CGD: Chronic granulomatous disease [4] C. Casimir, M. Chetty, M. C. Bohler et al., “Identification of the NADPH: Nicotinamide adenine dinucleotide phosphate defective NADPH-oxidase component in chronic granuloma- CRP: C-reactive protein tous disease: a study of 57 European families,” European Journal ESR: Sedimentation rate of Clinical Investigation,vol.22, no.6,pp. 403–406, 1992. Hgb: Hemoglobin [5] “Chronic granulomatous disease,” in Hematology: Basic Prin- WBC: White blood cell ciples and Practice,R.Hoffman, Ed., Churchill Livingstone, DHR: Dihydrorhodamine Philadelphia, Pa, USA, 2009. NBT: Nitroblue tetrazolium. [6] S. M. Holland, “Chronic granulomatous disease,” Clinical Reviews in Allergy and Immunology,vol.38, no.1,pp. 3–10,2010. [7] D. Roos, D. B. Kuhns, A. Maddalena et al., “Hematologically Disclosure important mutations: X-linked chronic granulomatous disease (third update),” Blood Cells Molecules and Diseases,vol.45, no. The authors have no na fi ncial relationships relevant to this 3, pp.246–265,2010. article to disclose. [8] H. Berendes, R. A. Bridges, and R. A. Good, “A fatal granulo- matosus of childhood: the clinical study of a new syndrome,” Minnesota Medicine,vol.40, no.5,pp. 309–312, 1957. Conflict of Interests [9] B. H. Landing and H. S. Shirkey, “A syndrome of recurrent infec- tion and infiltration of viscera by pigmented lipid histiocytes,” No authors have potential conflict of interests. Pediatrics,vol.20, no.3,pp. 431–438, 1957. [10] “Chronic granulomatous disease,” in Nelson Textbook of Pedi- atrics, R. Kliegman, Ed., Elsevier, Philadelphia, Pa, USA, 2011. Authors’ Contribution [11] R. L. Baehner and D. G. Nathan, “Quantitative nitroblue J. F. Moreau (B.A.) was the primary medical student who tetrazolium test in chronic granulomatous disease,” The New England Journal of Medicine,vol.278,no. 18,pp. 971–976, 1968. provided care to the subject of this paper. She draeft d the initial paper and approved the final paper as submitted. J. A. [12] C. L. Epling,D.P.Stites, T. M. McHugh,H.O.Chong,L.L. Blackwood, and D. W. Wara, “Neutrophil function screening Ozolek (M.D.) was the Pathologist who reviewed the biopsies in patients with chronic granulomatous disease by a flow of the subject of this paper while he was an inpatient. He cytometric method,” Cytometry,vol.13, no.6,pp. 615–620, 1992. provided the pathological images included within this paper [13] F. Morel, “Molecular aspects of chronic granulomatous disease. andbotheditedand approved thefinalpaper as submitted. P. ‘the NADPH oxidase complex’,” Bulletin de l’Academie Nationale L. Lin (M.D. and M.S.) has been the primary subspecialist for de Medecine,vol.191,no. 2, pp.377–392,2007. the subject of this paper since he was diagnosed with chronic [14] F. Defendi, E. Decleva, C. Martel, P. Dri, and M. J. Stasia, granulomatous disease. She edited and approved the n fi al “A novel point mutation in the CYBB gene promoter leading paperassubmitted.T.D.Green(M.D.)wastheImmunologist to a rare X minus chronic granulomatous disease variant— who consulted on this case while the subject of this paper impact on the microbicidal activity of neutrophils,” Biochimica wasaninpatient.Heeditedand approved thefinalpaper et Biophysica Acta,vol.1792, no.3,pp. 201–210, 2009. as submitted. E. A. Cassidy (M.D.) was the Rheumatologist [15] J. Rae, P. E. Newburger, M. C. Dinauer et al., “X-linked chronic who consulted on this case while the subject of this paper granulomatous disease: mutations in the CYBB gene encoding was an inpatient. She edited and approved the n fi al paper the gp91-phox component of respiratory-burst oxidase,” The as submitted. V. L. Venkat (M.D.) was the Gastroenterologist American Journal of Human Genetics,vol.62, no.6,pp. 1320– who consulted on this case while the patient was an inpatient. 1331, 1998. Sheeditedand approved thefinalcasereportassubmitted. [16] T. M. Rossi, J. Cumella, D. Baswell, and B. Park, “Ascites as a A. R. Buchert (M.D.) was the primary Inpatient Medical presenting sign of peritonitis in chronic granulomatous disease Provider forthe subjectofthispaper andalsofollowedthis of childhood,” Clinical Pediatrics,vol.26, no.10, pp.544–545, patient in diagnostic referral clinic until he was diagnosed 1987. Case Reports in Immunology 5 [17] S. Subramaniam, D. Tuman, A. R. Rausen, and S. D. Douglas, “‘Ascites’ and inguinal hernias: unusual presentation for chronic granulomatous disease of childhood,” eTh Mount Sinai Journal of Medicine,vol.41, no.4,pp. 566–569, 1974. [18] C. B. Foster, T. Lehrnbecher, F. Mol et al., “Host defense molecule polymorphisms influence the risk for immune- mediated complications in chronic granulomatous disease,” Journal of Clinical Investigation,vol.102,no. 12,pp. 2146–2155, [19] D. B. Kuhns, W. G. Alvord,T.Helleretal.,“Residual NADPH oxidase and survival in chronic granulomatous disease dou- glas,” eTh New England Journal of Medicine ,vol.363,no. 27,pp. 2600–2610, 2010. 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Chronic Granulomatous Disease Presenting as Aseptic Ascites in a 2-Year-Old Child

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Copyright © 2013 J. F. Moreau et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Publishing Corporation Case Reports in Immunology Volume 2013, Article ID 927897, 5 pages http://dx.doi.org/10.1155/2013/927897 Case Report Chronic Granulomatous Disease Presenting as Aseptic Ascites in a 2-Year-Old Child 1 2 3 4 5 J. F. Moreau, John A. Ozolek, P. Ling Lin, Todd D. Green, Elaine A. Cassidy, 6 7 Veena L. Venkat, and Andrew R. Buchert School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA Division of Pathology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Division of Infectious Disease, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Division of Pulmonary Medicine, Allergy and Immunology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Division of Rheumatology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Division of Gastroenterology, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA eTh Paul C. Gaffney Diagnostic Referral Service, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Correspondence should be addressed to Andrew R. Buchert; andrew.buchert@chp.edu Received 7 December 2012; Accepted 27 December 2012 Academic Editors: N. Kutukculer, C. Pignata, A. Plebani, and A. Vojdani Copyright © 2013 J. F. Moreau et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome that results from abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function. This defect leads to recurrent catalase-positive bacterial and fungal infections as well as associated granuloma formation. We review the case of a 2-year-old boy who presented with ascites and fever of an unknown origin as manifestations of CGD. Cultures were negative for infection throughout his course, and CGD was suspected aer ft identification of granulomas on peritoneal biopsy. Genetic testing revealed a novel mutation in the CYBB gene underlying his condition. This paper highlights the importance of considering CGD in the differential diagnosis of fever of unknown origin and ascites in children. 1. Introduction that occurs within 4 years of diagnosis (43%) [2]. Other pre- senting infections include osteomyelitis, liver and perirectal Chronic granulomatous disease (CGD) results from the abscesses, enteritis, and septicemia [1]. CGD can, in very rare inability of neutrophils to complete the rst fi step of the circumstances, present with ascites [3]. respiratory burst pathway, generation of superoxide, with The incidence of CGD is estimated to be between the downstream consequence of impaired microbe killing. 1/200,000 and 1/250,000 US births [2]. Most affected indi- CGD leads to recurrent and potentially lethal infections. viduals are male because approximately 70% of mutations Pneumonia is the most common infection before diagnosis are X-linked recessive; the remaining 30% of cases are (47%) [1] and occurs in the majority (79%) of patients within autosomal recessive [1, 2, 4]. In normal individuals, inflam- four years of diagnosis [2]. Lymphadenitis is the second matory stimuli prompt nicotinamide adenine dinucleotide most common infection before diagnosis (45%) [1], and phosphate (NADPH) oxidase (a lysosomal enzyme encoded subcutaneous abscess is the second most common infection on chromosome 22) to produce superoxide. Superoxide is 2 Case Reports in Immunology converted to hydrogen peroxide via superoxide dismutase Lyme disease, toxoplasmosis, Bartonella, cytomegalovirus, andthentohypochlorousacid(by myeloperoxidase),which and tuberculosis were also considered. Subsequent testing is lethal to bacteria [5]. Individuals with CGD are able to excluded these infectious entities. utilize hydrogen peroxide made by microbes and convert it to After a few days, he defervesced and was discharged home hypochlorous acid to preserve microbe killing, yet catalase- with presumptive diagnosis of a likely, yet to be diagnosed, positive bacteria can prevent this step by degrading the rheumatological disease. One month later, he developed per- hydrogen peroxide. us, Th catalase-positive organisms such sistent fever and abdominal distension. Exam was now sig- as Staphylococcus aureus are the most common microbial nificant for increased abdominal girth, and a u fl id wave was sources of infection; other common pathogenic organisms present on physical examination. Laboratory studies revealed in patients with CGD are Burkholderia cepacia, Nocardia, an increased platelet count (457× 10 /L) and ESR (74 mm/hr) Serratia,and Klebsiella [2, 6]. Approximately 70% of CGD as well as decreased ferritin (79.2 ng/mL) and Hgb (9.9 g/dL). cases are associated with mutations in the CYBB gene on the His albumin also remained low, prompting testing for preal- X chromosome, but well over 300 different CYBB mutations bumin (low at 5.6 mg/dL), proteinuria (negative), and protein have been reported in association with the disease [7]. In this losing enteropathy (alpha-1-antitrypsin normal (<20)). An paper, we describeanunusual case of CGDinachildwitha abdominal CT scan showed contour irregularity of the novel mutation in exon 13 of the CYBB gene who presented colon, ascites, and diffuse peritoneal enhancement with with an isolated lymphadenitis and months later developed fat stranding consistent with peritonitis. Paracentesis was ascites and culture-negative, granulomatous peritonitis. done, and cytological evaluation demonstrated purulent u fl id with large numbers of neutrophils and macrophages butnomalignant cells. Bacterialand fungal cultures were sterile. The serum-to-ascites albumin gradient was 1 g/L, 2. Case Report likely excluding portal hypertension as an etiology of the The patient is a 2-year-old male born to a G1P1 mother ascites. Gastrointestinal evaluation included esophagogastro- who had an uncomplicated pregnancy and delivery. His only duodenoscopy and colonoscopy with biopsies, endomysial signica fi nt past medical history was an isolated infection one antibody,amylase,and lipase.Duodenal,terminalileal,and and a half years earlier. His parents noticed a swollen area colonic biopsies were unremarkable and without villous on his neck near his left ear and took him to our tertiary abnormalities, inflammatory lymphoid cells, or accumulation care children’s hospital for evaluation. On admission, he was of pigmented macrophages; the other studies were likewise ∘ 9 febrile to 39.3 C and had a leukocytosis of 20 × 10 /L. A normal.Bonemarrowbiopsywasunremarkable,andatagged diagnosis of lymphadenitis was made. A culture of the uid fl WBC scan demonstrated no specific abnormal foci of uptake. drained from the abscess grew methicillin-sensitive S. aureus, His abdomen remained distended, but the girth was stable. butthe blood culturewas negative.Hewas discharged home He defervesced on ampicillin/sulbactam and metronidazole on amoxicillin/clavulanate. eTh neck swelling returned after and was discharged home to complete an empiric course of a few days despite oral antibiotics, prompting his parents antibiotics for peritonitis. to bring him back to the hospital. The abscess was drained One week later, he again developed persistent fever and for the second time, and he was administered intravenous increasing abdominal distension and pain, resulting in his ampicillin/sulbactam. With subsidence of the swelling, the refusal to walk. An exploratory laparoscopy revealed massive patient was discharged home to complete a 10-day course of ascites and an inflamed and friable peritoneum studded antibiotics and had no recurrence of the abscess. with yellow and white nodules. The ascitic uid fl was sent In September 2011, he was admitted with nearly one for culture, and biopsies of the peritoneum were taken. month of daily fevers up to 39.4 C. His only other symptoms The ascitic uid fl had 1500 WBCs but was sterile. Pathology were intermittent dysuria and slightly loose stools at normal of the peritoneal biopsies revealed acute and organizing frequency (1-2 times daily). Family history of immunological, peritonitis with granulomatous features but no evidence of hematological, and oncological diseases was negative. There fungal, acid-fast, or bacterial microorganisms (Figure 1). The was no recent travel. Physical exam was within normal granulomatous nature of the peritonitis prompted evaluation limits except for poor weight gain (decline from 36th to 7th for CGD. A dihydrorhodamine (DHR) test was performed percentile from 12 months of age to admission (28 months)). to assess oxidase burst capability and resulted in negligible Abnormal laboratory values included albumin 2.8 g/dL fluorescence, consistent with CGD. Genetic testing revealed (3.8–5.4 g/dL), alkaline phosphatase 509 IU/L (<290 IU/L), hemizygosity for the c.1683dupG mutation in exon 13 of the C-reactive protein (CRP) 10.69 mg/dL (0.08–1.2 mg/dL), CYBB gene. erythrocyte sedimentation rate (ESR) 131 mm/hr (0– 20 mm/hr), ferritin 178.1 ng/mL (10–60 ng/mL), hemoglobin (Hgb) 10.7 g/dL (11.5–13.5 g/dL), hematocrit 30.5% (34.0– 3. Discussion 40.0%), lactate dehydrogenase 258 IU/L (<171 IU/L), platelets 9 9 399 × 10 /L (156–369 × 10 /L), and neutrophils 57% (12– CGD was first described in 1957 independently by Berendes 34%). All other laboratory values were within normal et al. [8] and by Landing and Shirkey [9]asalethal limits. eTh differential diagnoses included Kawasaki disease, disease in males associated with increased susceptibility hematological malignancy, early juvenile idiopathic arthritis to infection and pigment-containing macrophages in the or other rheumatologic process, and intestinal infection. visceral organs. eTh pigment forms as macrophages clear Case Reports in Immunology 3 (a) (b) (c) Figure 1: (a) Biopsy of peritoneal nodules demonstrated a cellular and organizing peritonitis including neutrophils, mesothelial cells, and abundant macrophages some with epithelioid features (HE, 200x). Focal areas had relatively well-organized granulomas (b) with macrophages that did not express the activated macrophage marker CD163 (c) ((b); HE, 200x, (c); CD163, 200x). neutrophils that have undergone apoptosis, with subsequent 20% and 5%, resp.) [1, 2, 4, 13]. Rac2 (on chromosome 22) cytoplasmic accumulation of ceroid pigment, hence their andp40phox (NCF4geneonchromosome22) arethe other golden or orange-brown color by light microscopy [10]. In the 2 NADPH oxidase subunits, and mutations have thus far not 1960s and 1970s, defective NADPH oxidase was found to be been associated with CGD. the cause of CGD, leading to development of the nitroblue We describe a child with CGD who presents with a rare tetrazolium (NBT) test for diagnosis [11, 12]. A few decades constellation of fever of an unknown origin, ascites, and later, the DHR was developed as more quantitative measure culture-negative peritonitis. To our knowledge, this is the of oxidative burst, and it is now the preferred test for CGD rfi st reported case of CGD associated with a c.1683dupG [12]. Since then, over 400 mutations coding for the NADPH mutation in the CYBB gene [14, 15]. The c.1683dupG mutation oxidaseenzymehavebeendiscovered, andgenetic testingfor in the CYBB gene causes a frameshift mutation that results CGD has become available. in formation of a stop codon and thus loss of normal protein function. Ascites has rarely been reported as a presenting sign Cases of CGD have been associated with defects in of chronic granulomatous disease, and, in all of the previously genes encoding 4 of the 6 NADPH oxidase subunits, named reported cases, bacterial cultures were positive [3, 16, 17]. Our with reference to their molecular mass (kd) and “phox” patient did have nonspecific findings that are oen ft present for phagocyte oxidase. Flavocytochrome b558 is the redox in patients with CGD (fever, microcytic anemia, failure to center of NADPH oxidase and is composed of gp91phox thrive). Whilehehad asomewhatcomplicated lymphadenitis and p22phox. Defects in the X-linked gene encoding gp-91 in the past, he lacked other infections and the chronicity (CYBB) account for about 70% of known mutations causing typical of patients with CGD. CGD, and autosomal recessive p22phox mutations (CYBA gene on chromosome 16) account for an additional 5%. P47- This paper highlights the importance of considering phox (NCF1geneonchromosome7)and p67phox(NCF2 chronic granulomatous disease in the differential diagnosis of gene on chromosome 1) are both regulatory proteins that have fever of unknown origin and ascites. With a broad differential also been associated with autosomal recessive defects (about diagnosis and little direct evidence of CGD before peritoneal 4 Case Reports in Immunology biopsy, our patient reflects the challenge of making this with chronic granulomatous disease. He edited and approved diagnosis. The previously unreported mutation discovered the n fi al paper as submitted. in this patient may have been responsible for his unique clinical presentation. Past research has found that specific References genetic polymorphisms are associated with development of gastrointestinal inflammation and rheumatologic disorders [1] B. Martire, R. Rondelli, A. Soresina et al., “Clinical features, in CGD patients [18]. Otherworkhas shownthatthe long-term follow-up and outcome of a large cohort of patients with chronic granulomatous disease: an Italian multicenter quantity of residual neutrophil reactive oxygen intermediates study,” Clinical Immunology, vol. 126, no. 2, pp. 155–164, 2008. produced in CGD patients is mutation related and correlates [2] J. A. Winkelstein, M. C. Marino, R. B. Johnston et al., “Chronic with clinical outcomes [19]. In this context, knowing patient granulomatous disease: report on a national registry of 368 genotype may enable clinicians to provide improved care and patients,” Medicine,vol.79, no.3,pp. 155–169, 2000. is an area that we feel deserves further investigation. [3] M.Castro, L. Balducci,C.Ciueff tti, V. Lucidi,A.Torre,and S. Bella, “Ascites as an unusual manifestation of chronic granu- lomatous disease in childhood,” Pediatria Medica e Chirurgica, Abbreviations vol. 14,no. 3, pp.317–319,1992. CGD: Chronic granulomatous disease [4] C. Casimir, M. Chetty, M. C. Bohler et al., “Identification of the NADPH: Nicotinamide adenine dinucleotide phosphate defective NADPH-oxidase component in chronic granuloma- CRP: C-reactive protein tous disease: a study of 57 European families,” European Journal ESR: Sedimentation rate of Clinical Investigation,vol.22, no.6,pp. 403–406, 1992. Hgb: Hemoglobin [5] “Chronic granulomatous disease,” in Hematology: Basic Prin- WBC: White blood cell ciples and Practice,R.Hoffman, Ed., Churchill Livingstone, DHR: Dihydrorhodamine Philadelphia, Pa, USA, 2009. NBT: Nitroblue tetrazolium. [6] S. M. Holland, “Chronic granulomatous disease,” Clinical Reviews in Allergy and Immunology,vol.38, no.1,pp. 3–10,2010. [7] D. Roos, D. B. Kuhns, A. Maddalena et al., “Hematologically Disclosure important mutations: X-linked chronic granulomatous disease (third update),” Blood Cells Molecules and Diseases,vol.45, no. The authors have no na fi ncial relationships relevant to this 3, pp.246–265,2010. article to disclose. [8] H. Berendes, R. A. Bridges, and R. A. Good, “A fatal granulo- matosus of childhood: the clinical study of a new syndrome,” Minnesota Medicine,vol.40, no.5,pp. 309–312, 1957. Conflict of Interests [9] B. H. Landing and H. S. Shirkey, “A syndrome of recurrent infec- tion and infiltration of viscera by pigmented lipid histiocytes,” No authors have potential conflict of interests. Pediatrics,vol.20, no.3,pp. 431–438, 1957. [10] “Chronic granulomatous disease,” in Nelson Textbook of Pedi- atrics, R. Kliegman, Ed., Elsevier, Philadelphia, Pa, USA, 2011. Authors’ Contribution [11] R. L. Baehner and D. G. Nathan, “Quantitative nitroblue J. F. Moreau (B.A.) was the primary medical student who tetrazolium test in chronic granulomatous disease,” The New England Journal of Medicine,vol.278,no. 18,pp. 971–976, 1968. provided care to the subject of this paper. She draeft d the initial paper and approved the final paper as submitted. J. A. [12] C. L. Epling,D.P.Stites, T. M. McHugh,H.O.Chong,L.L. Blackwood, and D. W. Wara, “Neutrophil function screening Ozolek (M.D.) was the Pathologist who reviewed the biopsies in patients with chronic granulomatous disease by a flow of the subject of this paper while he was an inpatient. He cytometric method,” Cytometry,vol.13, no.6,pp. 615–620, 1992. provided the pathological images included within this paper [13] F. Morel, “Molecular aspects of chronic granulomatous disease. andbotheditedand approved thefinalpaper as submitted. P. ‘the NADPH oxidase complex’,” Bulletin de l’Academie Nationale L. Lin (M.D. and M.S.) has been the primary subspecialist for de Medecine,vol.191,no. 2, pp.377–392,2007. the subject of this paper since he was diagnosed with chronic [14] F. Defendi, E. Decleva, C. Martel, P. Dri, and M. J. Stasia, granulomatous disease. She edited and approved the n fi al “A novel point mutation in the CYBB gene promoter leading paperassubmitted.T.D.Green(M.D.)wastheImmunologist to a rare X minus chronic granulomatous disease variant— who consulted on this case while the subject of this paper impact on the microbicidal activity of neutrophils,” Biochimica wasaninpatient.Heeditedand approved thefinalpaper et Biophysica Acta,vol.1792, no.3,pp. 201–210, 2009. as submitted. E. A. Cassidy (M.D.) was the Rheumatologist [15] J. Rae, P. E. Newburger, M. C. Dinauer et al., “X-linked chronic who consulted on this case while the subject of this paper granulomatous disease: mutations in the CYBB gene encoding was an inpatient. She edited and approved the n fi al paper the gp91-phox component of respiratory-burst oxidase,” The as submitted. V. L. Venkat (M.D.) was the Gastroenterologist American Journal of Human Genetics,vol.62, no.6,pp. 1320– who consulted on this case while the patient was an inpatient. 1331, 1998. Sheeditedand approved thefinalcasereportassubmitted. [16] T. M. Rossi, J. Cumella, D. Baswell, and B. Park, “Ascites as a A. R. Buchert (M.D.) was the primary Inpatient Medical presenting sign of peritonitis in chronic granulomatous disease Provider forthe subjectofthispaper andalsofollowedthis of childhood,” Clinical Pediatrics,vol.26, no.10, pp.544–545, patient in diagnostic referral clinic until he was diagnosed 1987. Case Reports in Immunology 5 [17] S. Subramaniam, D. Tuman, A. R. Rausen, and S. D. Douglas, “‘Ascites’ and inguinal hernias: unusual presentation for chronic granulomatous disease of childhood,” eTh Mount Sinai Journal of Medicine,vol.41, no.4,pp. 566–569, 1974. [18] C. B. Foster, T. Lehrnbecher, F. Mol et al., “Host defense molecule polymorphisms influence the risk for immune- mediated complications in chronic granulomatous disease,” Journal of Clinical Investigation,vol.102,no. 12,pp. 2146–2155, [19] D. B. Kuhns, W. G. Alvord,T.Helleretal.,“Residual NADPH oxidase and survival in chronic granulomatous disease dou- glas,” eTh New England Journal of Medicine ,vol.363,no. 27,pp. 2600–2610, 2010. 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