Heterozygous TREX1 p.Asp18Asn mutation can cause variable neurological symptoms in a family with Aicardi-Goutieres syndrome/familial chilblain lupus

Sir, we present the first case of Aicardi–Goutières syndrome (AGS) and familial chilblain lupus (FCL) in the same family as a result of the evaluation of a three-generation family with chilblains caused by a heterozygous TREX1 p.Asp18Asn mutation. AGS is a genetically determined early-onset encephalopathy that features acquired microcephaly, cerebral calcifications, leukodystrophy and cerebral atrophy, as well as chilblains (∼40%) [1, 2]. As previous reports have highlighted the phenotypic overlap, AGS is one of the important disorders for differential diagnosis of SLE [3]. To date, five genes responsible for AGS have been identified: TREX1, RNASEH2B, RNASEH2C, RNASEH2A and SAMHD1 [4, 5]. TREX1 and SAMHD1 are also responsible for FCL, a Mendelian-inherited chilblain lupus that is a rare cutaneous form of SLE and lacks neurological abnormalities [3, 6–8]. In spite of the similarities between AGS and FCL, the variation and continuity of the two conditions are unknown because of the extreme rarity. The proband, a 12-year-old girl, was born at 38 weeks after an uncomplicated pregnancy to unrelated parents. Her birth weight was 2840 g and no congenital infections were documented. From infancy, she had poor weight gain. Beginning at 1 year of age, she regularly developed severe chilblains on her fingers and toes during the winter. She had mental retardation (full-scale Intelligence Quotient 49) and short stature (−3.1 s.d.). Laboratory tests showed mild hypothyroidism with normal levels of serum immunoglobulins and complement; ANAs, aCLs, LA, cryoglobulin and cold agglutinin were all negative. A cranial CT scan revealed bilateral calcifications in the basal ganglia (Fig. 1A). Examinations and pedigree. (A) CT scan of the proband’s head revealed bilateral calcifications in the basal ganglia. (B) Pedigree of the family. The left sides of the symbols indicate the presence of neurological findings and the right sides indicate chilblains. Affected individuals are indicated by black symbols, and individuals in whom symptoms could not be determined are indicated by grey symbols. Molecular investigation of the TREX1 gene was used to identify family members heterozygous for the TREX1 p.Asp18Asn mutation (E+), and those with no TREX1 mutation (E−). (C) Molecular investigation of the TREX1 gene of the proband. The proband has a family history of early-onset chilblains that led to finger amputations in patients I-2, II-1 and II-3 (Fig. 1B). The mother of the proband had suffered from chilblains in winter since childhood but her symptoms had ameliorated with age. She never showed neurological symptoms. At the age of 47 years, a cranial CT scan revealed very mild bilateral calcifications in the basal ganglia, comparable to those of age-matched controls. The niece of the proband, a 6-year-old girl, has also suffered from chilblains in winter since infancy but lacks any evidence of neurological symptoms (FIQ 90), and her cranial CT scan was normal. This study was approved by the ethical committee of Kyoto University, and after obtaining written informed consent according to the Declaration of Helsinki, genes related to cold-induced inflammation, namely NLRP3, NLRP12 and the genes responsible for AGS were examined by direct sequencing of their exons and exon–intron boundaries. The heterozygous c.52G>A of TREX1 leading to p.Asp18Asn (rs121908117) was identified in the proband as well as in her mother and niece (Fig. 1C). The proband was diagnosed with AGS according to the diagnostic criteria [1], and her mother and niece were diagnosed with FCL. Genetic analysis of the family members showed complete penetrance of the TREX1 p.Asp18Asn mutation, except in patient IV-7 in terms of chilblains, whereas thorough neurological examinations were not performed because of lack of consent. The majority of AGS patients show autosomal recessive traits. In the dominant type of AGS because of a TREX1 mutation, the previously reported neurological findings associated with the p.Asp18Asn mutation ranged from normal to milder than the p.Asp200Asn and p.Asp200His mutations [3, 5–7, 9]. In the presented family, one of the three patients with the p.Asp18Asn mutation showed mild mental retardation and cerebral calcifications. All the reported patients with heterozygous TREX1 mutations suffered from chilblains or vasculitis compatible with AGS [3, 5–7, 9]. In our study, 10 of the 11 patients with the p.Asp18Asn mutation suffered from chilblains. Thus, the majority of patients with heterozygous TREX1 mutations have skin lesions, although the neurological complications vary among genotypes. The TREX1 protein is a major component of 3′ to 5′ exonucleases [4]. The main pathophysiological mechanism of AGS is the overproduction of type I IFN, caused by unprocessed DNA because of reduced TREX1 enzymatic activity [4]. The TREX1 p.Asp18Asn, p.Asp200Asn and p.Asp200His heterodimers were shown to lack enzymatic activity, and the more aggressive neurological phenotypes can be explained by the greater inhibitory effects on wild-type TREX1 by mutations at Asp200 than at Asp18 [10]. It is intriguing that AGS patients in general have a lower rate of chilblains than those carrying the p.Asp18Asn mutation. To our knowledge, a correlation has yet to be established between the severity of neurological and skin lesions in AGS patients. A further accumulation of AGS and FCL cases and a delineation of the pathophysiology underlying the respective disorders are needed to understand how TREX1 mutations result in the various clinical phenotypes of AGS and FCL. In conclusion, we present a three-generation Japanese family with AGS and FCL caused by a heterozygous TREX1 p.Asp18Asn mutation. The occurrence of AGS and FCL in the same family is noteworthy and points out the need for clinicians to carefully evaluate neurological complications in FCL patients. Funding: This work was supported by grants from the Japanese Ministry of Health, Labor, and Welfare [H23-ippan-nanchi-003, H22-ippan-nanchi-123]. Disclosure statement: The authors have declared no conflicts of interest.