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CASE-BASED REVIEW
Ahead of print publication  

Chronic granulomatous disease presenting with foot abscess caused by Serratia marcescens and autoimmune dactylitis


 Department of Pediatrics, Bharati Vidyapeeth University Medical College Hospital and Research Centre, Pune, Maharashtra, India

Correspondence Address:
Jitendra S Oswal,
Department of Pediatrics, Bharati Vidyapeeth University Medical College Hospital and Research Centre, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_188_19

  Abstract 


Chronic granulomatous disease (CGD) is an inherited neutrophil phagocytic function disorder leading to recurrent infections, granuloma formations, and rarely autoimmune diseases. We report a case of genetically proven autosomal recessive CGD in a child with a mutation in NCF2 gene resulting in p67phox defect presenting with foot abscess caused by Serratia marcescens and autoimmune dactylitis at the same time. The case emphasizes the importance to consider a primary immunodeficiency in patients with musculoskeletal manifestations who develop unusual or opportunistic infections. We also hope awareness among pediatricians may lead to increased recognition of the autoimmune manifestations of CGD.

Keywords: Chronic granulomatous disease, dactylitis, Serratia marcescens



How to cite this URL:
Kapur SV, Oswal JS, Bafna V, Viswanathan V. Chronic granulomatous disease presenting with foot abscess caused by Serratia marcescens and autoimmune dactylitis. Indian J Rheumatol [Epub ahead of print] [cited 2020 Feb 18]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=276554




  Introduction Top


Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder that results in defective phagocyte oxidative function responsible for generating reactive oxygen species.[1] Genetic analysis has revealed mutation in at least one of the five genes that encode the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex enzyme. CYBB gene mutation leading to a defective gp91phox results in X-linked CGD (XL-CGD). Mutations in CYBA, NCF-1, NCF-2, and NCF-4 result in autosomal recessive CGD (AR-CGD) due to deficiency of gp21phox, p47phox, p67phox, and p40phox proteins, respectively.[1],[2] CGD is genetically heterogeneous with XL-CGD being the most common type reported in developed countries, whereas AR-CGD is the most common subtype in countries with the high rates of consanguinity. The disease is characterized by recurrent bacterial and fungal infections with a predilection to catalase producing organisms. Autoimmune diseases have been reported to occur in approximately 10% of CGD patients in addition to infections and granuloma formation.[3] In this case report, an AR-CGD patient presenting with foot abscess caused by a catalase producing opportunistic organism Serratia Marcescens and autoimmune dactylitis at the same time is described.


  Case Report Top


A 4-year-old male child from Yemen, the second issue of a third-degree consanguineous marriage was admitted with a history of swelling of right foot and fingers of the left hand with multiple painful oral ulcers since 1 month. There was no history of fever, rash, morning stiffness, tuberculosis, or any other joint involvement. He had a significant history of multiple hospital admissions requiring prolonged parenteral antibiotic therapy. Birth history was not significant, and he was immunized as per schedule. His examination revealed failure to thrive, submandibular lymphadenopathy, hepatosplenomegaly, marked swelling and tenderness in the right mid-foot and dactylitis of all fingers (except thumb) of the left hand with restricted movements [Figure 1]. Investigations revealed anemia (hemoglobin = 8.8 g/dl), neutrophilic leukocytosis (white blood cell = 16,300/cmm n = 75%, L = 14%), normal absolute neutrophil count (12,225/cmm), normal absolute lymphocyte count (2282/cmm), and raised erythrocyte sedimentation rate (77 mm at the end of 1 h). HIV ELISA was negative. X-ray of the left hand revealed periarticular osteopenia with soft-tissue swelling which responded to naproxen. Magnetic resonance imaging of the right foot revealed soft-tissue swelling over dorsum of the first metatarsal and a developing abscess which was later drained. Pus culture grew S. marcescens for which appropriate antibiotics were given for 3 weeks. Excisional biopsy of the submandibular gland was suggestive of granulomatous necrotizing lymphadenitis [Figure 2]. GeneXpert test for Mycobacterium tuberculosis on lymph node tissue was negative. Serum immunoglobulin levels and lymphocyte subset analysis were normal. CGD was considered owing to the isolation of an unusual catalase producing organism S. marcesecens, granulomatous lymphadenitis with prior clinical history of multiple infections. The neutrophil oxidative burst function as assessed by dihydrorhodamine flow cytometry-based assay showed an abnormally low stimulation index of 0.56 (control 57.3%). Genetic testing confirmed a homozygous nonsense mutation in the NCF2 gene; c.574C>T causing P (GLN192Ter 77X) stop codon in p67phox protein which confirmed the diagnosis of AR-CGD. On discharge, antimicrobial prophylaxis (trimethoprim-sulfamethoxazole, fluconazole) and donor screening for bone marrow transplantation were initiated.
Figure 1: Dactylitis of fingers

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Figure 2: Hematoxylin-eosin stain of a lymph node shows noncaseating granulomas (arrows)

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  Discussion Top


There is a paucity of data on the incidence of CGD in India, while the estimated prevalence in the western countries is 1 in 250,000.[4] Although the overall incidence of the disease is low, part of this may be attributed to a lack of clinical awareness of primary immunodeficiency (PID) and resourceful laboratories. Early diagnosis can lead to access to treatment including bone marrow transplantation and interferon therapy.

In addition to playing a critical role in microbial killing, the NADPH oxidase complex enzyme plays a protective role in inflammation and autoimmunity.[5],[6] Infection profile of 38 Indian children diagnosed to have CGD in a tertiary center isolated Staphylococcus aureus, Pseudomonas species as the most common causative bacteria, Aspergillus as the most common fungus and lung, liver and lymph nodes being the most common organs affected.[7] Children with XL-CGD presented earlier and had a greater number of infections as compared to AR-CGD.[7] In addition, Rawat et al. reported that S. marcescens was not isolated from any of the patients from the study. Our patient presented with right foot abscess due to S. marcescens with no evidence of any osteomyelitis. However, along with the foot abscess, he had autoimmune dactylitis as musculoskeletal manifestations. Clinically, the course of dactylitis in our patient was likely of autoimmune origin given the periarticular osteopenia on imaging, the prompt response to anti-inflammatory drug, and the complete resolution prior to introducing antimicrobial treatment.

Systemic lupus erythematosus, discoid lupus erythematosus, antiphospholipid syndrome, autoimmune thrombocytopenia, rheumatoid arthritis, IgA nephropathy, sarcoidosis, and celiac disease are reported manifestations in CGD.[3],[8],[9] Our patient is rare because not only did he have autoimmune arthritis, which is rare in CGD, but he also developed foot abscess by S. marcescens at the same time.

To the best of our knowledge, this is the first case reported from India with genetically proven AR-CGD presenting both with autoimmune dactylitis and foot abscess caused by S. marcescens at the same time. [Table 1] presents the case reports in literature looking at S. Marcescens, musculoskeletal manifestations, and CGD. It is to be noted that most of the reports are in XL-CGD, and none of the reports are from India.
Table 1: Case reports of musculoskeletal manifestations of Serratia marcescens in chronic granulomatous disease

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  Conclusion Top


This case illustrates that musculoskeletal manifestations can be one of the presenting features of a PID. It will also help in the early diagnosis of varied infective and autoimmune presentations of CGD.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



[14]



 
  References Top

1.
Roos D. Chronic granulomatous disease. Br Med Bull 2016;118:50-63.  Back to cited text no. 1
    
2.
de Boer M, Hilarius-Stokman PM, Hossle JP, Verhoeven AJ, Graf N, Kenney RT, et al. Autosomal recessive chronic granulomatous disease with absence of the 67-kD cytosolic NADPH oxidase component: Identification of mutation and detection of carriers. Blood 1994;83:531-6.  Back to cited text no. 2
    
3.
de Ravin SS, Naumann N, Cowen EW, Friend J, Hilligoss D, Marquesen M, et al. Chronic granulomatous disease as a risk factor for autoimmune disease. J Allergy Clin Immunol 2008;122:1097-103.  Back to cited text no. 3
    
4.
Winkelstein JA, Marino MC, Johnston RB Jr., Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79:155-69.  Back to cited text no. 4
    
5.
Brown JR, Goldblatt D, Buddle J, Morton L, Thrasher AJ. Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD). J Leukoc Biol 2003;73:591-9.  Back to cited text no. 5
    
6.
Hultqvist M, Olofsson P, Holmberg J, Bäckström BT, Tordsson J, Holmdahl R. Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc Natl Acad Sci U S A 2004;101:12646-51.  Back to cited text no. 6
    
7.
Rawat A, Vignesh P, Sharma A, Shandilya JK, Sharma M, Suri D, et al. Infection profile in chronic granulomatous disease: A 23-year experience from a tertiary care center in North India. J Clin Immunol 2017;37:319-28.  Back to cited text no. 7
    
8.
Schmitt CP, Schärer K, Waldherr R, Seger RA, Debatin KM. Glomerulonephritis associated with chronic granulomatous disease and systemic lupus erythematosus. Nephrol Dial Transplant 1995;10:891-5.  Back to cited text no. 8
    
9.
Narsipur SS, Shanley PF. IgA nephropathy in a patient with chronic granulomatous disease. J Nephrol 2002;15:713-5.  Back to cited text no. 9
    
10.
Cansever M, Kirçil N, Koker Y, Patiroglu T. Chronic granulomatous disease in a boy who presented with dactylitis caused by Serratia. Curr Rheumatol Rep 2017;19:41.  Back to cited text no. 10
    
11.
Ben AC, Maalej B, Gargouri L, Turki F, Majdoub I, Keskes H, et al. Serratia marcescens osteomyelitis as the first manifestation of chronic granulomatous disease. Arch Pediatr 2014;21:754-6.  Back to cited text no. 11
    
12.
Salfa I, Cantarutti N, Angelino G, di Matteo G, Capo V, Farinelli G, et al. Serratia marcescens osteomyelitis in a newborn with chronic granulomatous disease. Pediatr Infect Dis J 2013;32:926.  Back to cited text no. 12
    
13.
Campos M, Rocha G, Cordeiro A, Lemos S, Paiva A, Silva I, et al. Serratia osteomyelitis and chronic granulomatous disease. Acta Med Port 2011;24:449-52.  Back to cited text no. 13
    
14.
Mayer CW, Bangash S, Bocchini JA Jr., Lowery-Nordberg M, Bahna SL. Serratia marcescens osteomyelitis in an infant. Allergy Asthma Proc 2006;27:544-8.  Back to cited text no. 14
    


    Figures

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    Tables

  [Table 1]



 

 
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