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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 4  |  Page : 247-249

Neonatal onset Aicardi-Goutières syndrome with congenital corneal edema, expanding the phenotype

1 Department of Pediatric Neurology, Rainbow Children's Hospital, Hyderabad, Telangana, India
2 Department of Neonatology, Rainbow Children's Hospital, Hyderabad, Telangana, India
3 Department of Pediatrics, Sai Ayush Children's Hospital, Hyderabad, Telangana, India

Date of Submission02-Jun-2021
Date of Decision09-Aug-2021
Date of Acceptance15-Nov-2021
Date of Web Publication29-Nov-2021

Correspondence Address:
Dr. Romit Jain
Department of Pediatric Neurology, Rainbow Children's Hospital, Hyderabad - 500 034, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_162_21

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Background: Type I interferonopathy is a group of autoinflammatory disorders associated with enhanced type I interferon levels, due to upregulation of activation mechanisms or downregulation of negative feedback. Aicardi-Goutières syndrome (AGS) is one of these conditions, characterized by encephalopathy that usually manifests in late infancy. A rarer presentation that mimics congenital trans-placentally acquired infection or a 'pseudo-TORCH' subtype has been described. Clinical Description: A boy of 36-week gestational age with intrauterine growth restriction, nuchal transparency and a normal antenatal microarray assay, was delivered by cesarean section for oligohydramnios and fetal distress. The baby cried at birth, but developed mild respiratory distress and was neurologically depressed. A congenital infection was considered in view of being hypoplastic small for date with microcephaly, encephalopathy, intracerebral calcifications, multiple congenital heart lesions, and hepatosplenomegaly. Bilateral corneal edema was noted. Management: Supportive treatment was initiated. Mother-baby serology for congenital infections was negative. Various differential diagnoses for pseudo ToRCH presentations were considered and genetic testing planned. Exome sequencing identified a homozygous, single base pair insertion (c. 56_57insG variant) in exon 2 of TREX1 gene on chromosome 3, previously reported in AGS. The baby did not survive, Conclusion: This paper describes the clinical approach that was used to establish diagnosis in a neonate with “pseudo ToRCH” phenotype. It also expands the clinical phenotype of AGS by reporting a hitherto undescribed ocular finding of congenital corneal edema.

Keywords: Corneal edema, pseudo-ToRCH, TREX1, type 1 interferonopathy

How to cite this article:
Jain R, Reddy SN, Rao Koneru SS, Konanki R. Neonatal onset Aicardi-Goutières syndrome with congenital corneal edema, expanding the phenotype. Indian Pediatr Case Rep 2021;1:247-9

How to cite this URL:
Jain R, Reddy SN, Rao Koneru SS, Konanki R. Neonatal onset Aicardi-Goutières syndrome with congenital corneal edema, expanding the phenotype. Indian Pediatr Case Rep [serial online] 2021 [cited 2022 Jan 20];1:247-9. Available from: http://www.ipcares.org/text.asp?2021/1/4/247/331368

Type I interferonopathy is a group of autoinflammatory disorders associated with enhanced type I interferon (INF-α) signaling, either due to upregulation of its activation mechanisms or downregulation of negative regulatory systems. This results in increased IFN levels in the serum and cerebrospinal fluid. Currently almost 40 conditions are recognized. Though the clinical phenotypes are heterogeneous, they all share a few common characteristics, referred to by some as the “clinical IFN signature”; early onset of skin vasculopathy with chilblains, livedo reticularis and panniculitis, central nervous system manifestations, and/or interstitial lung disease.

Aicardi-Goutières syndrome (AGS) is a rare genetic encephalopathy that was one of the first type-1 interferonopathy to be described in 2003, when an overlap of clinical manifestations was observed among it, congenital viral infections, and autoimmune disorders like systemic lupus erythematosus. AGS is characterized by intracranial calcifications, white matter disease, and cerebrospinal fluid (CSF) lymphocytosis. Onset is usually in late infancy and early childhood.[1]

We present a genetically diagnosed newborn with AGS born to a primigravida who remained unidentified in the antenatal period, but manifested at birth with a multi-systemic pseudo-ToRCH presentation, and describe the clinical approach used to establish the diagnosis. We also expand the clinical phenotype of AGS by reporting congenital corneal edema, a feature that has not been described earlier.

  Clinical Description Top

A male neonate born at 36 weeks of gestation was admitted with respiratory distress since birth. He was delivered by an emergency caesarean section, indicated for oligohydramnios and fetal distress. The baby cried immediately after birth. The antenatal history was significant. Amniotic chromosomal microarray has been performed and reported normal, when ultrasonography had detected intrauterine growth restriction with increased nuchal translucency. There was no maternal history of placental insufficiency, febrile illnesses, or prior abortions. The baby was the first in birth order, born to a third-degree-consanguineous couple. The family history was not contributory.

On examination, vitals were stable apart from mild respiratory distress and low oxygen saturation that was corrected with low flow of oxygen. He was small for gestational age (birth weight 1.8 kg, <3rd centile), with length 40 cm (<3rd centile), head circumference 30 cm (<3rd centile), and Ponderal index 2.5 (indicating a hypoplastic, small for date baby). He had a widely open anterior fontanelle (3 cm × 3 cm), widely separated cranial sutures, bilateral corneal whitish haze [Figure 1], and generalized petechiae. There was no overt facial dysmorphism. The cardiovascular examination revealed a grade 3 pan-systolic murmur at the left upper sternal border. No abnormalities were detected in the respiratory system. The liver and spleen were enlarged. He was lethargic, had a poor cry, and decreased state-to-state variability, and poor spontaneous eye-opening. Neonate was hypotonic, with good anti-gravity movements and normal deep tendon reflexes, suggestive of central hypotonia. The neonatal reflexes (Moro's, palmar and plantar grasp, rooting, and sucking) were depressed. A provisional clinical diagnosis of a congenital infection was considered, and supportive management initiated.
Figure 1: Bilateral corneal opacities

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Management and outcome

Investigations were planned accordingly. Chest radiograph was normal. Salient blood reports included thrombocytopenia (platelet count 18,000/mm3), raised C-reactive protein (24 mg/dl), mild transaminitis (SGPT 143 IU/L, SGOT 288 IU/L). There was no anemia, and the blood glucose, serum electrolytes and renal function tests were normal. Calcium and phosphorus were normal and serum alkaline phosphatase was 157 IU/L. A small patent foramen ovale (PFO), 2.9 mm patent ductus arteriosus), and large peri-membranous ventricular septal defect (VSD) with bidirectional shunt were detected on echocardiography. Cranial ultrasonogram showed periventricular, basal ganglia, and thalamic hyperechogenic lesions [Figure 2]. Magnetic resonance imaging of the brain revealed simplified gyral pattern, periventricular, basal ganglia, and thalamic T2 hypointense lesions with blooming on the susceptibility-weighted image, suggestive of calcifications [Figure 3], and small hemorrhages in the occipital horns of lateral ventricles. An ophthalmological examination confirmed bilateral, symmetrical, diffuse corneal edema [Figure 1], which precluded a detailed retinal examination. Brainstem evoked response audiometry (BERA) was normal.
Figure 2: Cranial ultrasonogram (coronal section) showing intracranial calcifications

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Figure 3: T2 weighted Magnetic Resonance Imaging (axial view) with hypodense peri-ventricular calcifications (thin arrows) and gyral simplification (thick arrows)

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The paired ToRCH serology immunoglobulin (Ig) G and IgM for baby and mother was negative, as was the baby's urinary polymerase chain reaction for Cytomegalovirus. In view of the pseudo ToRCH presentation, the possibility of AGS was considered. Other differentials that were actively kept in view of the workup so far, included band-like calcification polymicrogyria syndrome (due to OCLN mutation), peroxisomal disorders, and mitochondrial cytopathies. A lumbar puncture was not done due to the thrombocytopenia. Genetic testing was planned. Clinical exome sequencing revealed a homozygous single base pair insertion in exon 2 of the TREX1 gene (chr3:g. 48466711_48466712insG; depth: 213x). This results in a frame-shift and premature truncation of the protein 82 amino acids downstream to codon 20 (p.Glu20GlyfsTer82; ENST00000625293.3). The variant has been previously reported (c. 58_59insG) in a patient diagnosed as AGS.[2] It was planned to give the baby zidovudine (off-label use), but the baby expired.

  Discussion Top

Initially a congenital infection was considered as the first differential, due to the combined presence of microcephaly, encephalopathy, intracerebral calcifications, and hepatosplenomegaly. Once the pseudo ToRCH clinical phenotype became apparent the differentials changed to AGS, Cockayne syndrome, hypoparathyroidism, pseudohypoparathyroidism, mitochondrial encephalopathies, biotinidase deficiency, and carbonic-anhydrase II deficiency.[3] Out of these a few were disregarded as they did not fit the clinical, biochemical and radiological profile. AGS was the top-most contender and was confirmed on genetic testing. Ocular manifestations like aniridia and congenital glaucoma have been described in AGS previously.[3] Diffuse, bilaterally symmetric corneal edema has never been reported before. We hypothesize that the corneal edema may result from immune-mediated inflammatory response, as has been reported in neonatal lupus presentation of AGS.[4]

The seven genes known to be associated with AGS include TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7).[5] Various genotype-phenotypes correlations have been described; prenatal-onset (TREX1, RNASEH2A, and RNASEH2C), classical/late infantile-onset (RNASEH2B, SAMHD1, and ADAR1), bilateral striatal necrosis (ADAR1), hereditary spastic paraparesis (ADAR1, IFIH1, and RNASEH2B), and SAMHD1-related cerebrovascular disease.[5],[6] The “pseudo-ToRCH” phenotype forms a significant proportion (28%), with antenatal-onset in a smaller sub-group.[7] All these genes are involved in nucleic acid metabolism. Any mutation is associated with upregulation of INF which can be measured as INF level in the CSF or as expression of INF stimulated genes in the blood in response to retro-elements.[6] Most cases of AGS are autosomal-recessive. De-novo mutations occur in very few patients.

As AGS shows characteristics of both autoimmunity and auto-inflammation in response to retro-elements, targeted treatment options include immunomodulation by steroids, Azathioprine, Intra-venous Immune globulin, Anti-INF α antibody, and reverse transcriptase inhibitors (RTIs). Among anti-INF therapies, Janus Kinase (JAK1/2) inhibitor (Ruxolitinib) has shown promising results.[8]. A single-center pilot study demonstrated improvement in the INF scores in patients with AGS given a combination of three RTIs (Abacavir, Lamivudine, and Zidovudine) for 12 months.[9]

With rapid advances in understanding pathophysiology and potential therapeutic options, a high index of suspicion for AGS is needed in an infant manifesting with a “pseudo-ToRCH” presentation. Establishing the diagnosis by appropriate genetic testing helps to provide appropriate genetic counseling to the family, including recurrence risk and antenatal diagnosis in subsequent pregnancies.

Declaration of patient consent

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

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Crow YJ, Vanderver A, Orcesi S, et al. Therapies in Aicardi-Goutières syndrome. Clin Exp Immunol 2014;175:1-8.  Back to cited text no. 1
Crow YJ, Hayward BE, Parmar R, et al. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet 2006;38:917-20.  Back to cited text no. 2
Musalem HM, Dirar QS, Al-Hazzaa SA, et al. Unusual association of aniridia with Aicardi-Goutières syndrome-related congenital glaucoma in a tertiary care center. Am J Case Rep 2018;19:500-4.  Back to cited text no. 3
Ramantani G, Kohlhase J, Hertzberg C, et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Arthritis Rheum 2010;62:1469-77.  Back to cited text no. 4
Livingston JH, Crow YJ. Neurologic phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières syndrome and beyond. Neuropediatrics 2016;47:355-60.  Back to cited text no. 5
Crow YJ, Shetty J, Livingston JH. Treatments in Aicardi-Goutières syndrome. Dev Med Child Neurol 2020;62:42-7.  Back to cited text no. 6
Crow YJ, Chase DS, Lowenstein Schmidt J, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A 2015;167A: 296-312.  Back to cited text no. 7
Fetter T, Smith P, Guel T, et al. Selective janus kinase 1 inhibition is a promising therapeutic approach for lupus erythematosus skin lesions. Front Immunol 2020;11:344.  Back to cited text no. 8
Rice GI, Meyzer C, Bouazza N, et al. Reverse-transcriptase inhibitors in the Aicardi-Goutières syndrome N Engl J Med 2018;379:2275-7.  Back to cited text no. 9


  [Figure 1], [Figure 2], [Figure 3]


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