A 31-Year-Old Man With a Ring-Enhancing Brain Lesion

Dr. Riley: A 31-year-old man with a history of appendicitis, bilateral femoral head avascular necrosis, impaired vision, headache, irritability, and pedal edema presented with a new-onset seizure. At age 21 years, he underwent emergent appendectomy. Around that time, he developed blanchable angiomata over his left shoulder after sun exposure. Eight months later, he required total hip replacement for bilateral femoral head avascular necrosis. His vascular risk factors were rare intranasal cocaine use and smoking a half pack of cigarettes daily. At age 26, he developed scotoma in his left visual field. At age 28, he experienced severe weekly migraines without aura. At age 30, he developed an irritable mood, pedal edema, and visual blurring, and “dark spots” in his right visual field. He had no other medical history and took no medications. The patient's family history was notable for cirrhosis and a reported diagnosis of an astrocytoma in his father. At age 27, his father had developed hypertension and gastrointestinal bleeding with abnormal liver function; he had an unremarkable hepatitis screen, ceruloplasmin level, and 24-hour urinary copper. Endoscopy showed esophageal varices, and angiography revealed portal hypertension. Liver biopsy showed cirrhosis of likely postnecrotic origin without iron or copper deposition. At age 31, his father developed headaches and complex partial seizures, at which time brain computed tomography (CT) showed a left frontal lobe mass. Cerebral angiography did not show a tumor blush. The brain mass was surgically resected and demonstrated necrosis and gliosis without evidence of malignancy. However, sites in the lesion bed not clearly part of the primary mass were reported as showing partial replacement by a Grade II astrocytoma with focal necrosis. The brain mass was presumed to be an astrocytoma, and he was treated with radiation therapy. Seizures were controlled, but he subsequently developed liver failure and died later that year. Upon presentation, our patient was hypertensive (170/90) and febrile (38.9°C). Examination was notable for lethargy, equally reactive pupils, bilateral pedal edema, and 3+ reflexes without Babinski sign. Initial laboratory evaluation revealed leukocytosis of 19,000 cells/mL, creatinine of 1.69 mg/dL (normal: 0.60–1.23 ng/dL), and elevated liver enzymes. Brain MRI was performed. Dr. Blitz: MRI with contrast demonstrates a rim-enhancing lesion in the subcortical region of the left temporal–occipital junction (Fig. 1A). This lesion is surrounded by hyperintensity indicative of edema in the fluid-attenuated inversion recovery image (Fig. 1B). Diffusion-weighted imaging shows central restricted diffusion in the lesion (Fig. 1C).FIG. 1.: A. Postcontrast axial T1 MRI shows a ring-enhancing lesion (arrow) in the left posterior temporal lobe measuring 18 × 21 × 11 mm in the craniocaudal, anterior-posterior, and transverse dimensions, respectively. B. Axial fluid-attenuated inversion recovery image sequence demonstrates significant T2-prolongation surrounding the left posterior temporal lesion (arrows), representing vasogenic edema. C. Axial diffusion-weighted imaging reveals restricted diffusion in the central aspect of the lesion (arrow), confirmed on ADC map (not shown).Dr. Riley: The patient was placed on anticonvulsants and broad-spectrum antibiotics for a possible brain abscess. In the meantime, blood and serologic studies revealed an erythrocyte sedimentation rate of 52 mm per hour and a C-reactive protein of 4.23 mg/L (normal: < 2.9 mg/L). Angiotensin-converting enzyme, anticardiolipin antibody, antinuclear antibody, anti-Jo 1 antibody, antiscleroderma 70 antibody, anti-Smith antibody, anti-U1 ribonucleoprotein antibody, Sjogren syndrome A/B immunoglobulin G (IgG), anti–double-stranded DNA antibody, rheumatoid factor, myeloperoxidase IgG, serine 3 protease IgG, B2 glycoprotein IgG/IgM, and serum protein electrophoresis were negative. It was elected to resect the brain mass due to a high suspicion for a neoplasm. Dr. Herlitz: There is extensive coagulative necrosis with a focus of organizing hematoma and severe vasculopathic changes, including hyalinization, fibrosis, thrombosis, and fibrinoid necrosis. A few chronic inflammatory cells are seen within vessel walls, but no granulomatous or neoplastic processes are identified (Fig. 2). These findings were more suggestive of vasculopathy than vasculitis. Serum and tissue cultures were negative, so antiviral and antibiotic agents were discontinued.FIG. 2.: Brain biopsy. A. There is extensive coagulative necrosis of brain parenchyma with many macrophages and a focus of organizing hematoma (trichrome, ×630). B. Blood vessels demonstrate different, prominent, histologic abnormalities including hyalinization, fibrosis, thrombosis, and fibrinoid necrosis. Few chronic inflammatory cells are seen within the vessels wall, but granulomas are not found (trichrome, ×400).Dr. Moazami: Neuro-ophthalmologic examination revealed that the patient's visual acuity was 20/20, right eye, and 20/50, left eye. Color vision was 4/6 AO-HRR plates in each eye. Visual field testing revealed patchy areas of loss in all quadrants bilaterally. Pupillary reactions to light and near were normal; there was no relative afferent pupillary defect. Extraocular movements were full. Slit-lamp examination revealed no abnormalities. Intraocular pressures were normal. Funduscopic examination revealed multiple cotton-wool spots and focal intraretinal periarteriolar transudates with markedly narrowed arterioles (Fig. 3A, B). Fluorescein angiography showed significant vascular dropout with an enlarged foveal avascular zone (Fig. 3C). Optical coherence tomography showed retinal nerve fiber layer thinning. The clinical presentation was thought to be most consistent with multiple branch retinal artery occlusions.FIG. 3.: A. Funduscopy reveals multiple cotton wool spots (arrows) and diffuse arteriolar narrowing in the right (A) and left (B) eyes. C. There is significant retinal vascular dropout on fluorescein angiography of the left eye.Dr. Radhakrishnan: Postoperatively, nicardipine drip was required for blood pressure control, and blood pressure was labile on amlodipine, labetalol, and losartan. The patient had subnephrotic proteinuria of approximately 1 g per day with benign urinary sediment. His creatinine subsequently normalized. Urine metanephrines were normal. Renal ultrasound showed normal-appearing kidneys. A tubulointerstitial or microvascular disorder was suspected, and renal biopsy was recommended. Dr. Herlitz: Renal biopsy shows endothelial cell swelling, duplication of glomerular basement membranes, mesangiolysis, and ischemic wrinkling of glomerular basement membranes (Fig. 4). There is no evidence of an immune complex-mediated glomerulonephritis or glomerular capillary fibrin thrombosis. One small artery shows marked endothelial swelling and vessel wall edema. This type of endothelial injury has a wide differential diagnosis, including the subacute phase of thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, malignant hypertensive nephrosclerosis, drug-induced endothelial injury, and hereditary endotheliopathies.FIG. 4.: Renal biopsy. A. A markedly abnormal glomerulus features swelling of endothelial cells, lysis of the glomerular mesangium, and prominent duplication of the glomerular basement membranes (arrows) (Jones methenamine silver, ×600). B. Electron microscopy reveals a glomerular capillary showing detachment of the endothelium from the glomerular basement membrane and widening of this subendothelial space by electron lucent material (arrows). Swollen endothelial processes also can be seen to fill the glomerular capillary lumen (×6,000). C. Arterioles are markedly abnormal showing swollen and reactive endothelial cells with a “hobnail” appearance (arrows). The myocytes surrounding this damaged endothelium are separated by prominent edema (Jones methenamine silver, ×200). (Courtesy of Dominick Santoriello, MD, Department of Pathology, Columbia University Medical Center).Dr. Riley: The patient's seizures were managed without recurrence. He had grossly normal cognition with a Montreal Cognitive Assessment score of 29/30. Visual symptoms and headaches improved, although daily headaches rapidly recurred. Fatigue, anxiety, and depression were treated with mirtazapine and clonazepam. One month after the renal biopsy, the patient developed flank pain and a distended abdomen. Transaminitis was still present and there was an elevated lipid panel with normal triglycerides. Abdominal CT, MRI, and ultrasound showed changes consistent with cirrhosis of the liver, portal hypertension, splenomegaly with splenic varices, and trace ascites. He had an unremarkable hepatitis panel, with normal ferritin and ceruloplasmin levels. Dr. Sampson: The patient was evaluated for an inherited vasculopathy after vasculitides were excluded by biopsy lacking inflammatory infiltrate. Metabolic work-up gave normal results, including venous lactate, pyruvate, creatine kinase, and urine organic acids. Alpha galactosidase testing was performed because his spider angiomata and ischemic stroke were suggestive of Fabry disease but was negative. The Columbia Combined Genetic NextGen sequencing Panel identified a heterozygous insertion of 4 nucleotides (AGAG) resulting in a serine to arginine transversion and frameshift mutation starting at position 322 in the TREX1 gene (p.S322Rfs), prematurely terminating transcription. Although this is a previously unreported variant, TREX1 truncation mutations are reported in retinal vasculopathy with cerebroleukodystrophy (RVCL). Final Diagnosis Retinal vasculopathy and cerebroleukodystrophy. RVCL is an autosomal dominant, microvascular, multiorgan endotheliopathy with onset in middle age. Other names for RVCL include “hereditary endotheliopathy with retinopathy, nephropathy, and stroke” (HERNS) (1); “hereditary vascular retinopathy” (2,3); and “cerebroretinal vasculopathy” (4,5). The TREX1 gene encodes a ubiquitously expressed 3′-5′ exonuclease (6). Although the exact pathophysiology of RVCL is unknown, disease-causing mutations are thought not to impair the exonuclease enzymatic function but rather to prevent its interaction with SET proteins that direct it toward DNA damaged by oxidative stress (5). It is hypothesized that disease is caused by either a failure of granzyme A–mediated cell death induced by TREX1/SET complexes (7) or the effects of untethered TREX1 protein (5). The vascular changes are similar to those seen after radiation damage (8), suggesting involvement of DNA repair mechanisms in pathogenesis. Thus, it may be advisable to limit radiation exposure for RVCL patients, as in ataxia telangiectasia. Dr. Riley: RVCL causes a diffuse microangiopathy with thickened and multilaminated subendothelial basement membranes (1). The predilection for infarctions in the brain, retina, and kidney has not been explained. Neurologically, RVCL causes a multi-infarct syndrome characterized by multiple subcortical, contrast-enhancing, white matter lesions. Symptoms include migraine-like headaches, psychiatric disturbances, and progressive neurologic deterioration. Ophthalmologic findings include retinal capillary dropout, vascular tortuosity, microaneurysms, and telangiectasias. Renal involvement causes hypertension and proteinuria. RVCL is an autosomal-dominant disease and can present with tumefactive brain lesions (1,9). The proband's father carried the diagnosis of astrocytoma, although his brain mass was primarily necrotic. An asymptomatic first-degree relative was later detected to have retinopathy. RVCL has been previously reported to mimic a brain tumor in multiple generations of a family (10), and it is likely that our patient's father also suffered from the RVCL and did not have an astrocytoma. Our patient expands the established phenotype of RVCL because he presented with cirrhosis, appendicitis, and femoral head avascular necrosis likely caused by the same vasculopathy. Although appendicitis is common, femoral head avascular necrosis is rare in the absence of other known risk factors. Our patient developed cirrhosis a month after his seizure, and his negative evaluation for other etiologies suggested that the same ischemic process was at fault. The patient's father also had cirrhosis and liver failure, so cirrhosis is likely among their RVCL manifestations. Our patient's phenotype suggests that RVCL can cause a systemic vasculopathy affecting the liver, intestine, and bone in addition to the brain, retina, and kidney. Elements of this expanded phenotype have been previously reported. In one report, 2 siblings with RVCL had bilateral osteonecrosis, and one had cirrhosis (11). Another case series described several patients with elevated gamma-glutamyl transpeptidase and alkaline phosphatase with normal transaminases, and one patient with hepatic fibrosis on autopsy without clinical symptoms of cirrhosis (4,9). Systemic basement membrane abnormalities have been found in the appendix on autopsy of patients with RVCL (1), but appendicitis has never been reported. In summary, we report a case of RVCL caused by a novel mutation in the TREX1 gene. Our case potentially expands the established phenotype of stroke, retinopathy, and nephropathy to include hepatocellular disease, intestinal infarctions, and avascular necrosis of the femoral head. RVCL is a systemic vasculopathy, and its manifestations are more protean than formerly appreciated.

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