A TREX1 mutation causing cerebral vasculopathy in a patient with familial chilblain lupus

Abstract

The patient regularly developed chilblains on her fingers and toes, particularly prominent during the winter beginning at 1 year of age (Fig. 1a). At 18, 19 and 21 years of age, she suffered from cerebral infarctions. At 21 years of age, the patient presented with digital gangrene that subsequently led to finger amputation. A skin biopsy suggested small vessel angitis. Steroid therapy was administered and the chilblain improved. The dose of prednisolone was gradually decreased from 30 mg/day. At 28 years of age, the patient presented with left hemiparesis while being treated with 7.5 mg/day of prednisolone. The patient was alert and at presentation there was no finding suggestive of encephalopathy. Brain magnetic resonance imaging (MRI) disclosed an infarction in the internal capsule. Three-dimensional computed tomography angiography (3D-CTA) demonstrated multiple cerebral aneurysms (Fig. 1b). She had no history of either cocaine use or other stimulant drug abuse. Ophthalmic examinations showed no finding of retinal vasculopathy. Laboratory investigations were unremarkable, except for the presence of antinuclear antibodies, with a titer of 1:20 and a speckled pattern. A hypercoagulable panel (lupus anticoagulant and anticardiolipin antibody titers, the protein C and S levels and the antithrombin III level) and tests for cryoglobulinemia were negative. A cerebrospinal fluid (CSF) examination revealed an increased interleukin-6 (IL6) level of 37.9 pg/ml (normal range B4.3 pg/ml). The dose of prednisolone was increased to 60 mg/day. After 2 months, 3D-CTA showed reduced cerebral aneurysms (Fig. 1c). At 29 years of age, the patient presented with dysarthria after the dose of prednisolone was reduced to 5 mg/day. Brain MRI revealed a thalamic infarction (Fig. 1d). Old small infarctions were observed on T2-weighted images (Fig. 1e–g). 3D-CTA demonstrated no obvious cerebral aneurysms. However, a detailed evaluation of cerebral angiography demonstrated multiple small aneurysms (Fig. 1h). The dose of prednisolone was increased to 15 mg/day. After 1 month, a CSF examination showed a decreased IL-6 level of 7.6 pg/ml. The patient’s mother, grandmother, brother and sister also had chilblains starting in early childhood (Fig. 1i). However, none of them had any history of stroke except for the grandmother, who had died from a subarachnoid hemorrhage at 45 years of age. Blood samples for a genetic analysis were collected from the patient and other family members with a history of chilblains. We performed direct sequencing of all coding exons of TREX1. A heterozygous TREX1 p.Asp18Asn mutation was identified in the present family (Fig. 1j). Chilblain lupus erythematosus is a rare chronic form of cutaneous lupus erythematosus characterized by coldinduced skin lesions in acral locations that usually affect middle-aged females [1]. A familial form of chilblain lupus manifesting in early childhood was first described by LeeKirsh et al. in 2006 [2]. To date, heterozygous mutations in TREX1 [3–7] and SAMHD1 [8] have been reported in patients with familial chilblain lupus (FCL). TREX1 is the major 30 ? 50 exonuclease in mammalian cells. Mutation of TREX1 results in accumulation of altered DNA, which triggers an abnormal innate immune response [3, 4]. Mutations in TREX1 are also responsible for autoimmune diseases including systemic lupus erythematosus, K. Yamashiro (&) R. Tanaka Y. Li M. Mikasa N. Hattori Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan e-mail: kazuo-y@juntendo.ac.jp