Chronic granulomatous disease (CGD) is a primary immunodeficiency that results in dysfunctional phagocytic leukocytes, leaving the host susceptible to a variety of pathogens.1 Symptoms include recurrent, life-threatening bacterial and fungal infections and associated widespread granulomatous inflammation, affecting multiple organ systems from childhood. Chorioretinal lesions, first described in 1965,2 are the most common ocular manifestation of the disease and affect about 24% of patients with X-linked CGD.3 Other reported ocular signs include uveitis, keratitis, conjunctivitis, and optic nerve atrophy.3,4 Although the chorioretinal lesions are usually regarded as inactive, there is one report of retinal ischemia, neovascular membrane, vitreous hemorrhage, and macular edema.5 We report a case of CGD with atypical ocular manifestations.
A 2-year-old male was referred for “retinal spots” and elevated intraocular pressure (IOP) in both eyes. The patient's medical history revealed osteomyelitis of a phalanx at 1 month of age, leading to a work-up and diagnosis of X-linked CGD by flow cytometric dihydrorhodamine (DHR) neutrophil respiratory assay and subsequent genetic testing.
Examination of the anterior segment revealed an enlarged cornea in the right eye. The cornea was clear in both eyes without the presence of Haab's striae. The anterior chamber angle was open with visualization of the ciliary body band in both eyes and a normal iris insertion. An increased cup-to-disc ratio (C/D) was noted in the right eye (C/D: 0.6), whereas the left optic disc appeared normal (C/D: 0.3). IOPs were 33 mm Hg in the right eye and 9 mm Hg in the left eye, with axial length measurements of 24.49 mm in the right eye and 21.96 mm in the left eye.
Funduscopic examination revealed scattered hypo- and hyperpigmented retinal lesions in a perivascular distribution sparing the macula (Figures 1A and 1B). Fluorescein angiography (FA) revealed staining of the retinal lesions, pruning of the peripheral capillary tree, and peripheral avascular retina (Figures 2A and 2B).
Color fundus photograph of the right eye (A) and left eye (B) show a cup-to-disc ratio of 0.6 and 0.3, respectively. Both eyes (A, B) show bilateral hypo- and hyperpigmented retinal lesions scattered diffusely but with a predilection for perivascular distribution and sparing the macula.
Fluorescein angiography centered at the macula of both the right (A) and left (B) eyes reveal staining of some active lesions and blocked fluorescence of other atrophic lesions. There are no chorioretinal lesions in the macula. Peripheral shots of the right (C) and left (D) eyes show pruning of the peripheral capillary tree (arrow) and an avascular retina (asterisk).
The patient was started on IOP-lowering drops in the right eye and the following week a 360° trabeculotomy was successfully performed on the right eye.
CGD is caused by a defect in nicotinamide adenine dinucleotide phosphate oxidase multiprotein enzyme complex resulting in failure of the phagocytic leukocytes to kill pathogens. Without the respiratory burst, these pathogens survive to become chronic infections and are walled off into granulomas by macrophages. A defect in CYBB (cytochrome B, b subunit), located on the X chromosome, is the most common defect, accounting for 50% to 70% of cases.6 The diagnosis of CGD can be made by testing the activity of the phagocytes by the NBT reduction test or flow cytometric DHR neutrophil respiratory burst assay.7
The retinal lesions in CGD are classically described as inactive punched-out atrophic chorioretinal scars with pigment clumping around vessels and retinal pigment epithelium (RPE) atrophy. Histologic studies in enucleated eyes with CGD lesions demonstrate RPE hypertrophy and hyperplasia surrounded by RPE and retinal atrophy with foci of chronic inflammatory cells — without organsims.8 Previous reports have suggested that these chorioretinal lesions do not progress and do not affect visual acuity.8,9 However, Kim et al. described two cases of vision loss due to vitreous hemorrhage from peripheral neovascularization and avascular peripheral retina.5
To our knowledge, there have been no previous reports of CGD-associated elevated IOP and glaucoma. We detected peripheral avascular retina in both eyes without evidence of neovascularization in the setting of unilateral glaucoma (Figure 2). The patient underwent a successful trabeculotomy in the right eye. Kim et al. performed widefield FA in 12 patients with childhood glaucoma and found 91% of eyes to have peripheral retinal nonperfusion.10 We feel that, given the symmetry of the peripheral nonperfusion in both eyes in this case, it is most likely a manifestation of CGD and not due to glaucoma.
The current treatment of CGD includes long-term antibiotics and antifungals. Recent reports suggest that patients undergoing hematopoietic stem-cell transplant (HSCT) have increased survival and lower rate of severe infections as well as hospital admissions when compared to patients managed conservatively.12 Importantly, HSCT is indicated early in the course of the disease to prevent infections, excessive inflammation, and end-organ damage.12 HSCT was recommended for the patient in this case.
We report a case of unilateral glaucoma in a patient with CGD and bilateral avascular retina without evidence of neovascularization. This case suggests that careful IOP measurements and periodic surveillance of patients with CGD with wide field angiography is advisable to detect possible complications and preserve vision.
- Beghin A, Comini M, Soresina A, et al. Chronic granulomatous disease in children: A single center experience. Clin Immunol. 2017;188:12–19. doi:10.1016/j.clim.2017.11.016 [CrossRef]
- Carson MJ, Chadwick DL, Brubaker CA, Cleland RS, Landing BH. Thirteen boys with progressive septic granulomatosis. Pediatrics. 1965;35:405–412.
- Goldblatt D, Butcher J, Thrasher AJ, Russell-Eggitt I. Chorioretinal lesions in patients and carriers of chronic granulomatous disease. J Pediatr. 1999;134:780–783. doi:10.1016/S0022-3476(99)70299-4 [CrossRef]
- Valluri S, Chu FC, Smith ME. Ocular pathologic findings of chronic granulomatous disease of childhood. Am J Ophthalmol. 1995;120(1):120–123. doi:10.1016/S0002-9394(14)73773-0 [CrossRef]
- Kim S, Kim J, Yu Y. Chorioretinal lesions in patients with chronic granulomatous disease. Retina. 2003;23(3):360–365. doi:10.1097/00006982-200306000-00012 [CrossRef]
- Roos D, Kuhn DB, Maddalena A, et al. Hematologically important mutations: The autosomal recessive forms of chronic granulomatous disease. Blood Cells Mol Dis. 2010;44:291–299. doi:10.1016/j.bcmd.2010.01.009 [CrossRef]
- Yu JE, Azar AE, Chong HJ, Jongco AM 3rd, Prince BT. Considerations in the diagnosis of chronic granulomatous disease. J Pediatric Infect Dis Soc. 2018;7(suppl_1):S6–S11. doi:10.1093/jpids/piy007 [CrossRef]
- Rodrigues MM, Palestine AG, Macher AM, Fauci AS. Histopathology of ocular changes in chronic granulomatous disease. AM J Ophthalmol. 1983;96(6):810–812. doi:10.1016/S0002-9394(14)71932-4 [CrossRef]
- Baechner RL. Chronic granulomatous disease of childhood: Clinical, pathological, biochemical, molecular and genetic aspects of the disease. Pediatr Pathol. 1990;10(1–2):1433.
- Kim HY, Hodapp E, Grajewski AL. Peripheral retinal vasculopathy in childhood glaucoma. Retina. 2015;35(5):1028–1035. doi:10.1097/IAE.0000000000000415 [CrossRef]
- Djalilian AR, Smith JA, Walsh TJ, Malech HL, Robinson MR. Keratitis caused by Candida glabarata in a patient with chronic granulomatous disease. Am J Ophthalmol. 2011;132(5):782–783. doi:10.1016/S0002-9394(01)01091-1 [CrossRef]
- Åhlin A, Fasth A. Chronic granulomatous disease – conventional treatment vs. hematopoietic stem cell transplantation: an update. Curr Opin Hematol. 2015;22(1):41–45. doi:10.1097/MOH.0000000000000097 [CrossRef]