A 31-year-old Chinese male with sudden onset of blurred vision in his right eye for 2 days was referred to our clinic on January 21, 2019. On examination, best corrected visual acuity (BCVA) was 20/20 and 20/1,000 in the left and right eye, respectively. Furthermore, intraocular pressure (IOP) was elevated to 39.3 mmHg in the right eye. A slit lamp demonstrated ciliary hyperemia, positive fresh keratic precipitates (KP), positive anterior chamber flare and cell, and positive relativistic afferent pupillary disorder (RAPD) in the right eye. On fundus examination, the right eye showed prominent white sheathing of retinal venules and, to a lesser extent, arterioles in all the quadrants, resembling the appearance characterized as "frosted branch angiitis." Supratemporal retinal hemorrhages indicated concomitant branch retinal vein occlusion (BRVO). Moreover, macular edema and disc hyperemia were presented (Figure 1A). Fundus photograph of the left eye showed normal appearance (Figure 1B). Optical coherence tomography (OCT) suggested macular edema (Figure 1D). Fluorescein angiography (FA) revealed supratemporal bleeding-blocked fluorescence, concomitant capillary non-perfusion zone, and extensive dye leakage from vessels and the optic disc (Figures 1G,H). Positive anterior chamber flare and cells, together with retinal exudation and macular edema, also indicated panuveitis.
The patient has a history of intermittent and recurrent fever, skin rash (Figure 1C), and aphthous ulcer from 5 years ago. Tests from other hospitals implicated hypogammaglobulinemia with immune globulin (Ig) G 4.520 g/l, IgA 4.632 g/l, and IgM 0.134 g/l. One month ago, the patient visited a neurology clinic with complaints of dizziness, nausea, vomiting, totter, and slurred speech. Magnetic resonance imaging (MRI) revealed lacunar infarction in the right basal ganglia and the lateral ventricle (Figure 1E). Activated partial thromboplastin time (APTT) was mildly prolonged to 50.3 s. CBC showed elevated neutrophil percentage (NEU%) of 88.1% and decreased lymphocyte (LYM#) of 0.45 x 109/L. Hepatorenal function, cranial angiography, carotid and cardiac ultrasound, and dynamic electrocardiogram were uneventful. Because of self-claimed allergy to aspirin, patient was administered clopidogrel and atorvastatin once a day.
With consultation from neurologists and rheumatologists, the following laboratory investigations were carried out: raised C reactive protein (CRP) of 41.2 mg/l, homocysteine of 16.0 mumol/l, decreased CD25 + lymphocyte of 4.06%, helper T-cell of 3.70%, IgG of 4.3 g/l, IgA of 0.48 g/l, and IgM of <0.25 g/l, and microcytic hypochromic anemia was noticed. Other workups, including urine routines, erythrocyte sedimentation rate (ESR), coagulation function, streptolysin O, rheumatoid factor, antiphospholipid antibodies, antineutrophilic cytoplasmic antibodies, antinuclear antibodies, protein C, protein S, Toxoplasma gondii, rubella, herpes simplex, hepatitis B, hepatitis C, Epstein-Barr virus, HIV, cytomegalovirus, Treponema pallidum, and Mycobacterium tuberculosis, were negative. Anterior chamber paracentesis for high-throughput sequencing did not find any pathogenic microorganisms.
Oral methylprednisolone 24 mg/day was started and tapered off within 3 months, together with three times of periocular injection of 20 mg methylprednisolone. Topical fluorometholone (0.1%) and pranoprofen (0.1%) eye drops four times per day were administered. Carteolol (2%) and brinzolamide (1%) eye drops were used to alleviate IOP. Focal retinal photocoagulation and intravitreal injection of ranibizumab (0.5 mg/50 mul) were given to control fundus hemorrhage. One week after treatment, KP and aqueous flare and cells disappeared and the IOP decreased back to normal. One month later, the macular edema was resolved in the right eye (Figure 2D). White sheathing of the vessels alleviated (Figure 2A). Two months later, a fundus photo showed full resolution of vascular sheathing (Figure 2B) and visual acuity improved to 20/133. Retinal hemorrhage was absorbed at 5 months follow-up (Figure 2C).
However, the patient came to our emergency room (ER) with a complaint of left limb weakness and deterioration of slurred speech for 3 days, 5 months after being diagnosed of FBA. APTT was prolonged by 47.8 s, F XI and F XII activity was decreased to 66.7% (reference range: 70-120%) and 6.6% (reference range: 70-150%), respectively. MRI confirmed fresh lacunar infarction in the right pons (Figure 1F). The patient was diagnosed with patent foramen ovale (PFO) by contrast echocardiography of the right heart during admission and underwent a catheter-based closure surgery then. One month later, our patient was admitted in the emergency department of another center, complaining aggravation of left limb weakness and slurred speech. Due to the recent cardiac surgical implantation, cranial computerized tomography (CT) was adopted instead of MRI, which implicated low-density focus of the right pons. Considering deteriorating strokes under clopidogrel and atorvastatin intervention, 1.5-2.25 mg oral warfarin was given to prevent cryptogenic stroke, with international normalized ratio (INR) maintained between 2 and 3. One month later, the patient appeared with progressive dizziness and tinnitus and was diagnosed of sudden hearing loss of the left ear. Then, the patient presented with diplopia associated with palsy of the left trochlear nerve. Given the patient's complicated multiple disorders, whole exome sequencing (WES) was adopted to explore the possible pathogenesis. Several deletion mutations of ADA2 (homozygous deletion of exon 7 and heterozygous deletion of exons 2-6 and 8-10) and heterozygous mutation of F12 (p.K365Qfs*69) were recognized. Subsequent laboratory test demonstrated a total ADA activity of 2.2 U/l and an ADA2 activity of 0 U/l. Anti-TNF therapy was then started by weekly injection of 50 mg etanercept. Meanwhile, the patient received intravenous immunoglobulin according to monitoring. The brief timeline of our case is described in Figure 3.