Manifestation of Panuveitis after Intraocular Surgery in a Child with Blau Syndrome.

Blau syndrome (BS) is a rare granulomatous disease with autosomal dominant inheritance. It is characterized by a triad of dermatitis, arthritis, and recurrent uveitis. This case presents the onset of panuveitis in BS after intraocular surgery. A 10-year-old boy presented to the outpatient clinic with retinal detachment in the left eye after 6 years following early-onset cataract surgery. Bilateral panuveitis occurred 3 weeks after surgical repair and resulted in a total visual loss in the left eye and was persistent to conventional treatment in the right eye. Genetic testing revealed a mutation in NOD2 gene. The addition of adalimumab to the treatment regimen resulted in long-term uveitis control and maintenance of 20/70 vision in the right eye. We propose that NOD2-mediated inflammatory cascade can be activated by intraocular surgery and results in the manifestation of BS. Copyright:

Introduction

Blau syndrome (BS) is a very rare familial granulomatous disease with autosomal dominant inheritance. It is characterized by a triad of symptoms, including skin rash, chronic symmetric arthritis, and recurrent uveitis.

The disease was first described by Blau in 1985,[1] followed by a report of a similar family by Jabs in the same year.[2] Through linkage analysis of a large BS pedigree, the disease locus was mapped to the chromosomal region 16q12.1–13.[3] Mutations in the NOD2/CARD15 gene were found to be responsible for BS.[4] Although BS is considered an early-onset sarcoidosis (EOS), it is postulated that EOS is caused by sporadic mutations in NOD2 gene.

In this case, we describe onset of persistent panuveitis after 3 weeks following intraocular surgery, with subsequent genetic testing confirming the diagnosis of BS.

Case Report

A 10-year-old boy with no previous history of uveitis was referred to the Vitreoretinal Division of King Khaled Eye Specialist Hospital (KKESH) 2 years ago because of sudden drop of vision in the left eye 5 weeks before presentation. He had no previous attacks of skin rashes or arthritis. Family history of uveitis, joint, or skin diseases was negative. Past ocular history included lens aspiration and intraocular lens implantation 6 years earlier in both eyes, for early-onset cataract. On examination, the best-corrected visual acuity (BCVA) was 20/40 in the right eye and hand movement (HM) in the left eye. Anterior segment examination of both eyes revealed quite anterior chambers (ACs) with posterior chamber intraocular lenses in both eyes and normal intraocular pressure. Fundus examination was unremarkable in the right eye and revealed total rhegmatogenous retinal detachment (RD) with extensive proliferative vitreoretinopathy in the left eye. Pars plana vitrectomy with 360° retinectomy and silicone oil injection was performed in the left eye for the treatment of RD. Three weeks postoperatively, he presented with BCVA of 20/70 in the right eye and HM in the left eye. Biomicroscopic examination revealed 3+ AC reaction in both eyes and + 4 vitritis in the left eye with poor view to the fundus, while in the right eye, he had multiple distinct chorioretinal lesions with 1+ vitritis and peripheral focal vascular sheathing [Figure 1a]. Fundus fluorescein angiography (FFA) showed multiple early hypofluorescent areas, which were more numerous than the lesions seen clinically [Figure 1b]. These corresponded to hyperfluorescent areas in the later frames with peripheral vascular leakage [Figure 1c]. Uveitis workup including complete blood count, renal function tests, liver function tests, and chest computed tomography were within normal limits. Fluorescent treponemal antibody absorbed and purified protein derivative and tuberculosis Quantiferon Gold test results were negative. Serum angiotensin-converting enzyme level was 64 U/L (reference range: 13–100 U/L) and serum lysozyme result was 12.5 mg/L (reference range: 9.6 and 16.8 mg/L). The clinical impression was in favor of sympathetic ophthalmia and 3 doses of 1 g intravenous (IV) methylprednisolone daily were administered followed by oral prednisolone 1 mg/kg/day with weekly tapering and oral methotrexate 15 mg weekly. Panuveitis was controlled and choroidal lesions evolved into chorioretinal scars in the right eye but were resistant to treatment and resulted in no light perception in the left eye. Four months later, he presented with further reduced vision in the right eye to 20/125. The right eye showed new development of macular chorioretinal lesions associated with diffuse areas of subretinal fibrosis [Figure 2a]. He was admitted for 3 doses of IV methylprednisolone followed by oral prednisolone on discharge and continued on oral methotrexate. Given the nature and distribution of choroidal lesions which were persistent to treatment, BS was suspected and next-generation sequencing was ordered. The test result revealed nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene with a heterozygous nucleotide substitution from C to T at position c.2798+158C>T in intron 8 (reference sequence NM_0022162.1). Subcutaneous adalimumab injections at 40 mg dosage every other week were initiated. Over the next 6 months, the choroidal lesions gradually scarred [Figure 2b] and vision improved to 20/70. The patient was maintained on 5 mg oral steroids, 15 mg oral methotrexate weekly, and every other week adalimumab without recurrence of uveitis or development of systemic manifestations of BS over 1-year follow-up. Examination of available family members including parents and two siblings did not reveal uveitis, skin, or joint abnormalities.

Figure 1

The clinical presentation of the right eye at the onset of BS panuveitis in a 10-year-old male. (a) Multiple distinct choroidal lesions with 1+ vitritis and peripheral focal areas of vascular sheathing (arrows). (b) Multiple early hypofluorescent areas which are more numerous than the lesions seen clinically. (c) Late hyperfluorescent areas corresponding to the lesions seen clinically with peripheral vascular leakage

Figure 2

Recurrence of the multifocal choroidal lesions in BS in a 10-year-old male patient. (a) Increase in the multifocal choroidal lesion while the patient was on tapered oral steroids and oral methotrexate. (b) Scarring of the lesions 6 months after initiation of systemic adalimumab

Discussion

BS is a rare inherited disease which manifests a variety of ophthalmic features including persistent panuveitis, band keratopathy, cataract, glaucoma, and RD. Although uveitis is the most common ophthalmic feature of BS, it was preceded by cataract and RD in our patient.[5] Corneal subepithelial opacifications and nummular keratitis can be the presenting ophthalmic manifestations of BS even before the onset of uveitis.[67] Although the absence of ocular inflammation or treatment use (including steroids) indicates that cataract was the presenting feature of BS in our patient, the exposure to cataract surgery before RD makes the association of BS with RD less certain.

The mechanism of uveitis in BS involves activation of the NOD2 which is expressed in vascular endothelial cells from the iris, choroid, or retina.[8] It plays a role in the innate immune system through the recognition of muramyl dipeptide (MDP).[9] NOD2 activates the nuclear factor κB mainly through serine/threonine kinase receptor-interacting protein-2 (RIP-2) or RIP-like interacting CLARP Kinase (RICK) and, in turn, promoting inflammatory processes.[8] A recent report showed the induction of ocular and systemic manifestations of BS by exposure to bacterial pneumonia.[7] This might be explained by the fact that MDP itself is a component of the bacterial cell wall. MDP activation of NOD2 can be induced by other cytokines including interferon-gamma (IFN-gamma).[8] Our patient might represent an example of this process because a high level of inflammatory cytokines including IFN-gamma levels was found following intraocular surgery.[10] Activated NOD2 through this pathway might have accelerated the onset of uveitis through the propagation of ocular inflammatory cascade. A subset of Crohn's disease which involves polymorphisms in NOD2 is associated with granuloma formation in the gastrointestinal tract.[911] Histopathologically, Blau granulomas display a distinct morphology characterized by large polycyclic granulomas with dense lymphocytic coronas, whereas Crohn's granulomas were isolated, with loose lymphocytic borders and sclerosis of surrounding tissues.[9]

Although NOD2 was found to induce interleukin-1 beta (IL-1B) production, ocular inflammation was independent of the level of IL-1B.[12] This explains why the treatment of patients with Anakinra which is an anti-IL-1 was not effective on the ocular component of BS.[12]

Addition of adalimumab to the management regimen of our patient resulted in good uveitis control and stabilization of visual acuity. Beneficial effects of adalimumab have been demonstrated previously.[6] Adalimumab exerts its action through inhibition of tumor necrosis factor-alpha (TNF-α). This might suggest a role of TNF-α in the induction of ocular component of BS.

Our findings suggest that NOD2 mutations could be found in sporadic BS cases even with previous exposure to exogenous factors. This, in turn, further indicates that BS might be an underdiagnosed disease. Furthermore, in spite of uveitis being a characteristic feature of BS, other ophthalmic manifestations might precede its onset. Better understanding of the inflammatory processes involved in BS can facilitate the decision-making regarding treatment options of these patients.

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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 initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.