Chronic granulomatous disease (CGD) is a rare disorder of phagocytic inability to produce the respiratory burst needed to kill ingested micro‐organisms.1 CGD typically presents early in life with recurrent life threatening bacterial and fungal infections and tissue granuloma formation.2 Prophylaxis with systemic antibiotics, antifungals, and interferon γ have been shown to significantly reduce infections.1,2 Ocular involvement occurs in about 25% of CGD patients. We report the clinicopathological findings of a subretinal CGD lesion.
Case report
A 4 year old boy developed recurrent, cultured positive, cutaneous bacterial infections (Serratia spp). Four years later, ocular examination revealed 20/200 in the right eye and 20/50 in the left eye, bilateral moderate vitritis, retinal oedema and pigmentary clumps, multiple chorioretinal scars, and a large chorioretinal scar in the left eye. Despite transient improvement on antibiotics and systemic and periocular corticosteroids, his vision became worse with persistent vitritis and retinal exudation in the left eye. Six months later the patient was found to have an abnormal nitroblue tetrazolium test diagnostic of CGD.
Another 6 months after the diagnosis of CGD he was referred to NIH where p47phox deficiency was detected.1 Evaluation revealed 20/100 in the right eye, 20/200 in the left, mild conjunctival injection, chemosis, 1+ anterior chamber flare in the both eyes, and trace cells in the left. Posterior segment showed bilateral 2+ vitreous cells and trace haze, disc hyperaemia and oedema, perivascular sheathing, peripheral chorioretinal scars, and bone spicules in both eyes (fig 1A). Additionally, the left eye showed diffuse retinal oedema with marked macular lipid exudation and an inferotemporal subretinal mass where a large chorioretinal scar had been noted previously (fig 1B). This mass was worrying for intraocular granuloma, abscess, or neoplasm. Fluorescein angiography showed generalised disc and retinal vascular leakage, and staining of the subretinal mass, which appeared solid and homogeneous with low to moderate reflectivity on ultrasonography.
Figure 1 Fundus photographs showing (A) vitreous haze, mild disc oedema and hyperaemia, diffuse retinal oedema and perivascular sheathing, pigment atrophy, and marked macular lipid exudation; and (B) a subretinal mass (asterisk) in the inferotemporal region, perivascular bone spicule, and intraretinal pigment migration in the left eye.
The biopsy of the intraocular mass revealed glial and vascular inflammatory granulation tissues admixed with abundant spindle cells stained positive for actin and myosin (fig 2). No granuloma or malignancy was identified. Special stains and cultures of the vitreous and biopsy were negative for bacteria and fungi. Vitreal interleukin‐6 (IL‐6) (141 pg/ml) and IL‐8 (26 pg/ml) were elevated.
Figure 2 Microphotographs showing the subretinal mass that is composed of (A) glial component (asterisk), a cluster of inflammatory cells and hyalinised fibrous stroma (two asterisks) admixed with pigment clumps and small vessels (haematoxylin and eosin, original magnification, ×100), (B) typical granulation tissue with proliferating capillaries and lymphoplasmacytic inflammatory cells in hyalinised stroma (haematoxylin and eosin, original magnification, ×400), and (C) local proliferation of smooth muscle highlighted by positive staining for myosin (black), a marker for smooth muscle within the fibrovascular tissue (avidin‐biotin‐complex immunoperoxidase with anti‐human myosin B antibody, original magnification ×200).
Postoperatively the patient developed a rhegmatogenous retinal detachment within a month and became blind in the left eye. The uveitis was controlled with prednisone and ciclosporin. Vision in the right eye maintained 20/80 without visual field or electroretinogram worsening during 3 years of follow up.
Comment
CGD with an incidence of 1/200 000 live births is caused by a congenital defect in phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase production of superoxide and related species.1 This multicomponent enzyme system is composed of cytosolic proteins (p47phox, and p67phox, p40phox, and rac1/2) and membrane proteins (gp91phox and p22phox that form cytochrome b558), which assemble at membrane sites upon cell activation.3 The X linked CGD is caused by mutation in gp91phox (60% of cases), while the autosomal recessive forms are caused by mutations in other genes.4 Patients with p47phox deficiency (30% of cases), as in our patient, often have a milder clinical course than patients with X linked defects.
Ophthalmic manifestations of CGD include blepharoconjunctivitis, keratitis, optic neuropathy, and chorioretinal scars.5,6,7 Active chorioretinal lesions, vitreous haemorrhage, and retinal detachment are noted infrequently.8 Anterior segment involvement is presumably caused by inadequate control of normal flora, whereas the chorioretinal lesions are hypothesised to be the sequelae of infectious microemboli or granulomas. Pathological studies of intraocular CGD specimens have not demonstrated micro‐organisms.9 Vitritis with active chorioretinal lesions progressing to panuveitis with an exudative retinal detachment has been reported in one CGD patient; histopathology of the eye showed chorioscleral granuloma.8
Another feature of CGD involves poor wound healing.10 Therefore, subretinal granulation tissue mass in our case may represent an abnormal reparative response to previous chorioretinal injury. The absence of infection or granuloma, intravitreal pro‐inflammatory cytokines, and improvement with immunosuppression suggests that his ocular disease is probably the result of aberrant inflammatory responses. Routine ocular biopsy is not recommended as part of standard ophthalmic evaluation.
Footnotes
Financial support: Intramural program of the National Eye Institute, NIH.
References
- 1.Segal B H, Leto T L, Gallin J I.et al Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore) 200079170–200. [DOI] [PubMed] [Google Scholar]
- 2.Johnston R B., Jr Clinical aspects of chronic granulomatous disease. Curr Opin Hematol 2001817–22. [DOI] [PubMed] [Google Scholar]
- 3.El‐Benna J, Dang P M, Gougerot‐Pocidalo M A.et al Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses. Arch Immunol Ther Exp (Warsz) 200553199–206. [PubMed] [Google Scholar]
- 4.Clark R A, Malech H L, Gallin J I.et al Genetic variants of chronic granulomatous disease: prevalence of deficiencies of two cytosolic components of the NADPH oxidase system. N Engl J Med 1989321647–652. [DOI] [PubMed] [Google Scholar]
- 5.Palestine A G, Meyers S M, Fauci A S.et al Ocular findings in patients with neutrophil dysfunction. Am J Ophthalmol 198395598–604. [DOI] [PubMed] [Google Scholar]
- 6.Goldblatt D, Butcher J, Thrasher A J.et al Chorioretinal lesions in patients and carriers of chronic granulomatous disease. J Pediatr 1999134780–783. [DOI] [PubMed] [Google Scholar]
- 7.Djalilian A R, Smith J A, Walsh T J.et al Keratitis caused by Candida glabrata in a patient with chronic granulomatous disease. Am J Ophthalmol 2001132782–783. [DOI] [PubMed] [Google Scholar]
- 8.Valluri S, Chu F C, Smith M E. Ocular pathologic findings of chronic granulomatous disease of childhood. Am J Ophthalmol 1995120120–123. [DOI] [PubMed] [Google Scholar]
- 9.Grossniklaus H E, Frank K E, Jacobs G. Chorioretinal lesions in chronic granulomatous disease of childhood. Clinicopathologic correlations. Retina 19888270–274. [DOI] [PubMed] [Google Scholar]
- 10.Eckert J W, Abramson S L, Starke J.et al The surgical implications of chronic granulomatous disease. Am J Surg 1995169320–323. [DOI] [PubMed] [Google Scholar]