Aicardi-Goutières syndrome (AGS): recurrent fetal cardiomyopathy and pseudo-TORCH syndrome
- 1 Neonatology, Rainbow Children's Hospital Banjara Hills, Hyderabad, India
- 2 Pediatric Cardiology, Rainbow Children's Heart Institute, Hyderabad, Telengana, India
- 3 Pediatric Neurology, Rainbow Children's Hospital Banjara Hills, Hyderabad, Telangana, India
- 4 Intensive Care, Rainbow Children's Hospital, Hyderabad, Andhra Pradesh, India
- Correspondence to Dr Nalinikanta Panigrahy; nalini199@gmail.com
Abstract
Aicardi-Goutières syndrome (AGS) induces innate immune activation. It can present with cerebral calcifications and hepatosplenomegaly mimicking congenital infections. The present case report discusses the diagnosis and treatment of a case of fetal cardiomyopathy whose postnatal symptoms resembled TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes and syphilis) infection. The mother had a history of two lost pregnancies due to fetal cardiomyopathy and the same was identified in the current pregnancy. At 34 weeks of gestation, the mother delivered a late preterm male neonate due to intrauterine growth restriction weighing 1590 g with respiratory distress and cardiomyopathy at birth. The neonate had cerebral calcifications, hepatosplenomegaly and thrombocytopenia. As the infant’s TORCH IgM titre was negative, pseudo-TORCH syndrome similar to AGS was suspected. Clinical exome sequencing of the parents and fetus identified no genes for hydrops fetalis or fetal cardiomyopathy; however, the AGS TREX1 gene was identified in the neonate, while additional symptoms resembled TORCH infection. The neonate was discharged and has shown improvement with oral baricitinib treatment for the last 9 months.
Background
Aicardi-Goutières syndrome (AGS; OMIM: 225750) is a heritable interferonopathy associated with systemic autoinflammation that causes elevated interferon (IFN) levels, central nervous system calcifications, leucodystrophy and severe neurological sequelae.1 A subgroup of infants with AGS present at birth with abnormal neurological findings, hepatosplenomegaly, elevated liver enzymes and thrombocytopenia, which is highly suggestive of congenital infection.2 Consequently, in such circumstances, the absence of definitive evidence of an infectious agent should raise suspicion of AGS. The diagnosis of AGS is based on suggestive clinical findings and characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leucodystrophic changes), and/or by the presence of one of the following: (a) biallelic pathogenic variants in ADAR, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1 or TREX1; (b) specific heterozygous autosomal dominant pathogenic variants in TREX1 and ADAR; and (c) a variety of heterozygous autosomal dominant pathogenic variants in IFIH1.2 Beyond cerebral calcification, there is little evidence of the prenatal phenotype of AGS.3 Here we present a neonatal case of AGS diagnosed with cardiomyopathy after 24 weeks’ gestation. The mother had a history of similar cardiomyopathy in two previous pregnancies. In addition to cardiac problems, the newborn exhibited multiple clinical and radiological markers of TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes and syphilis) syndrome within the first week of life. This case report demonstrates that AGS can present with fetal cardiomyopathy, and discusses its progression.
Case presentation
A late preterm male neonate weighing 1590 g was delivered by caesarean delivery at 34 weeks’ gestation due to intrauterine growth restriction (IUGR) and a Doppler abnormality (absent end-diastolic flow). The mother was in her 30s, was in a non-consanguineous marriage, was gravida 4 classification and had a healthy daughter. During the second pregnancy, the fetus was diagnosed with cardiomyopathy at 26 weeks and died of hydrops fetalis at 37 weeks. In the third pregnancy, fetal cardiomyopathy was detected at 20 weeks’ gestation and a spontaneous abortion occurred at 23 weeks. In the current pregnancy, the fetus was again diagnosed with cardiomyopathy with 34% left ventricular ejection fraction (LVEF) at 24 weeks using two-dimensional echocardiography (figure 1A and video 1), and fetal MRI showed an enlarged cisterna magna (figure 1B). Clinical exome sequencing was used to analyse blood samples of the father and mother, as well as amniocentesis samples. A genetics evaluation revealed no specific genes associated with the phenotype of hydrops fetalis, cardiomyopathy, mucopolysaccharidosis or collagen vascular disease. The TORCH infection, thyroid profile and lupus profile of the mother (anti-Ro and anti-La antibodies) were negative. The delivery was normal, and the neonate’s Apgar scores were 7 and 9 at 1 and 5 min, respectively. The newborn was admitted to neonatal intensive care unit (NICU) due to respiratory distress and hypoxaemia and was administrated 5 cm of nasal continuous positive airway pressure (CPAP). Microcephaly (24 cm head circumference), hepatomegaly (3 cm below the costal margin) and a systolic heart murmur were notable findings of the initial examination.
(A) Fetal two-dimensional echocardiography M mode shows cardiomyopathy with 34% left ventricular ejection fraction. (B) Fetal MRI shows prominent cisterna magna.
Investigations
The neonate had a Silverman-Andersen score of 4, and was stable on CPAP with 30% fraction of inspired oxygen and a respiratory rate of 50 breaths/min. A dobutamine infusion was initiated owing to cardiomyopathy and poor peripheral perfusion. Chest radiography showed a prominent cardiothymic silhouette and low lung volumes without any other signs of lung disease. Echocardiography performed at admission revealed mild left ventricular dysfunction, a 35% LVEF and non-compaction of the apex without calcifications. ECG results were normal. In the second week of life, a cardiac examination revealed biventricular dysfunction, a 30% LVEF and evidence of congestive heart failure (figure 2 and video 2). An initial complete blood cell count analysis showed an elevated white cell count of 39×109/L (N=4.5–17.5×109/L), with a lymphocyte predominance and low platelet count of 66×109/L (N=150–400×109/L). Serum electrolyte, lactate, ammonia and glucose levels were normal. Elevated aspartate aminotransferase and normal alanine aminotransferase levels were observed. Cranial ultrasonography at admission showed hyperechogenic basal ganglia, thalamic calcifications and subtle periventricular white matter calcification (figure 3A). We suspected possible congenital TORCH infection likely caused by toxoplasmosis or other agents, rubella, cytomegalovirus or herpes simplex virus. Single-donor platelet transfusions failed to improve thrombocytopenia; the lowest platelet count was 30×109/L. Intravenous immunoglobulin was administered to prevent antibody-mediated thrombocytopenia; however, there was no response. Abdominal ultrasonography revealed hepatosplenomegaly and minimal ascites without visceral calcifications. Brain CT showed periventricular calcifications and ventriculomegaly (figure 3B). Extended metabolic screening for amino acids and acyl carnitine, thyroid profiles and urinary organic acid levels was all normal. A cellular immunity defect evaluation revealed normal T-cell and B-cell counts as well as normal number of natural killer cells. An ophthalmology examination revealed no evidence of chorioretinitis. Brain MRI on day 21 of life showed polymicrogyria in the frontoparietal regions, rarefaction in the bilateral basal ganglia, and ventriculomegaly, a hypoplastic cerebellum, and intracranial calcifications (ICCs) in periventricular white matter (figure 4). The newborn’s TORCH IgG, IgM and urinary quantitative cytomegalovirus tests were negative. No pathogenic organisms were detected in the blood or cerebrospinal fluid (CSF) cultures. CSF was tested negative on a viral meningoencephalitis panel using PCR. When infectious aetiologies were excluded, the investigation shifted to genetic causes of TORCH-like syndromes and whole-exome sequencing was ordered. Exome sequencing detected a previously reported homozygous single base pair insertion in exon 2 of the TREX1 gene (chr3:g.48466711_48466712insG) that resulted in a frameshift and premature truncation of the protein 82 amino acids downstream of codon 20 (p.Glu20GlyfsTer82).4 The neonate’s unrelated parents were positive for the same heterozygous pathological variant mutation in exon 2 of the TREX1 gene.
Neonatal two-dimensional echocardiography confirms dilated cardiomyopathy with poor ventricular function.
(A) Cranial ultrasound on day 1 shows prominent basal ganglia, thalamus calcifications and periventricular white matter calcification. (B) Plain CT scan of the brain shows periventricular calcification and hydrocephalus.
MRI of the brain on day 21 shows polymicrogyria in frontoparietal regions, ventriculomegaly, hypoplastic cerebellum and calcifications of basal ganglia and in periventricular white matter area.
Differential diagnosis
Congenital TORCH infection can cause anaemia, thrombocytopenia, hepatosplenomegaly and cardiac symptoms; however, ICCs and microcephaly are especially notable in newborns. Some genetic disorders are characterised by ICCs, which are similar to congenital infections.5 After excluding congenital infections from the TORCH spectrum, the first step in the differential diagnosis of AGS is usually to rule out other illnesses associated with ICCs and early-onset encephalopathy. It is worth noting some cases described in the literature as independent clinical entities, such as microcephaly–intracranial calcification syndrome or pseudo-TORCH syndrome (table 1), suggestive of the early-onset neonatal forms of AGS.6 7 The major differential diagnoses of AGS are described in table 1. In addition to AGS, other known diseases that have been linked to mutations in the TREX1 gene include Cree encephalitis, familial chilblain lupus and retinal vasculopathy with cerebral leucodystrophy (RVCL).8 Heterozygous parents of children with AGS caused by TREX1 gene mutations may be at a risk of systemic lupus erythematosus or RVCL.9
Differential diagnosis of Aicardi-Goutières syndrome
| Differential diagnosis | Clinical features |
| TORCH syndrome | Identification of infections which can cause congenital/intrauterine infection such as toxoplasmosis, herpes, rubella, cytomegalovirus, syphilis, HIV and Zika virus |
| Pseudo-TORCH syndrome6 23–26 |
|
| Cerebral calcifications and leucodystrophy2 7 8 27–30 | Classic Cockayne syndrome (type 1) Neonatal lupus erythematosus Hoyeraal-Hreidarsson syndrome Mitochondrial cytopathies, 3-hydroxyisobutyric aciduria (OMIM: 236795); cerebroretinal microangiopathy with calcifications and cysts (Coats plus) (OMIM: 612199) Leucoencephalopathy, brain calcifications and cysts (Labrune syndrome) (OMIM: 614561) |
| TREX1 gene8 9 | Cree encephalopathy, familial chilblain lupus Retinal vasculopathy with cerebral leucodystrophy |
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TORCH, toxoplasmosis, other agents, rubella, cytomegalovirus, herpes and syphilis.
Considering the recurrent history of fetal cardiomyopathy, prenatal genetic testing of the parents and fetus was performed, which did not reveal any genetic abnormalities associated with a cardiomyopathy, arrhythmia panel or hydrops fetalis phenotype. Clinical exome sequencing of the mother for cardiomyopathy, arrhythmia, mucopolysaccharidosis, haemoglobinopathies, hydrops fetalis and other relevant investigations, such as collagen vascular disease, was done as per described differential diagnosis of fetal cardiomyopathy. Fetal cardiomyopathy was classified as dilated or hypertrophic. Dilated cardiomyopathy is characterised by reduced contractility (shortening fraction <28%) and ventricular enlargement >97.5% according to the normal standard for gestational age without thickening of the walls. TORCH infection is the most frequent cause. Some additional recognised causes of dilated cardiomyopathy include Barth syndrome, endocardial fibroelastosis (mumps), maternal anti-Ro/anti-La antibody (lupus and Sjogren’s syndrome), anaemia related to anti-C antibody, haemochromatosis and infantile arterial calcinosis. In addition, rare causes were Toriello-Carey syndrome, sarcolipin mutation, sialic acid storage disease, mitochondrial diseases, juxtaductal coarctation, and MC1 and MYH7 mutations. Hypertrophic cardiomyopathy is diagnosed when the parietal thickness is >97.5% of normal standard for gestational age. Diabetes mellitus is the most prevalent cause in mothers. Noonan syndrome (PTPN11, KRAS, SOS1 and RAF1 genes), LEOPARD syndrome (PTPN11 gene), trisomy 13, Hurler syndrome, ATPase deficiency, congenital glycosylation disorder type 1, congenital myotonic dystrophy, X linked myotubular myopathy, α-thalassemia and twin-to-twin transfusion are other known causes of hypertrophic cardiomyopathy.10–12 Clinical examination showed microcephaly, hepatosplenomegaly and signs of congestive heart failure. Laboratory workup showed thrombocytopenia, lymphocytic predominant leucocytosis and liver transaminitis. CSF workup ruled out bacterial and viral infections; however, IFN-α level was not estimated. Brain imaging showed cerebral calcifications, cerebellar hypoplasia and ventriculomegaly. Echocardiography revealed worsening cardiac function with non-obstructive cardiomyopathy. As the TORCH test was negative for the newborn, genetic cause of ICC such as pseudo-TORCH syndrome was considered and clinical exome sequencing was performed, which confirmed the diagnosis of AGS with homozygous mutation of the TREX1 gene.
Treatment
The prognosis of patients with AGS depends on the severity of symptoms, and treatment currently focuses on supportive care. There is no known preventive or definitive cure for AGS. Some individuals with AGS can survive for decades with mild and well-controlled symptoms. The neonate with AGS described here was discharged on low-flow oxygen at 37 weeks postmenstrual age. During the NICU stay, cardiac condition worsened further, and lowest LVEF of 21% was recorded. At discharge, the baby was on multiple cardiac medications such as digoxin, spironolactone, carvedilol and hydralazine. At infancy, he was hospitalised due to bronchiolitis and administered levetiracetam and clobazam owing to seizures. The successful use of Janus kinase inhibitors, such as ruxolitinib and baricitinib, to treat AGS was recently reported.13 14 Considering the disease progression, such as persistent seizures, development delay, a poor eye contact, a reticular skin pattern, oxygen dependency, a low cardiac output and persistent lymphocytic leucocytosis, the Janus kinase inhibitor baricitinib (0.2 mg/per kg body weight in two divided doses) was started at infancy, and it was tolerated well by the baby. Complete blood count, renal function and liver function tests were done weekly for 1 month and monthly for 6 months thereafter. Clinical improvements, such as a decreased oxygen requirement, less frequent seizure episodes, improved cardiac function and normalised prior leucocytosis, were observed after 9 months of baricitinib therapy.
Outcome and follow-up
Growth, neurodevelopment and neurological status of the newborn have been frequently assessed during the last 18 months. Growth failure, microcephaly, spasticity, dystonia, motor and cognitive development delay, poor vision and a speech delay were detected. After baricitinib use, oxygen requirement decreased, and the infant remained stable on room air as a toddler. His electroencephalogram seizure activity diminished, and he was weaned off of many anti-seizure medications. He is currently receiving a maintenance dose of levetiracetam. After treatment with baricitinib, the patient’s cardiomyopathy began to improve, with a 59% 0f LVEF as a toddler (figure 5 and video 3) and cardiac medicines no longer required. The respiratory parameters improved after 1 year, and oxygen therapy was no longer required. The patient had three episodes of lower respiratory tract infections with persistent lymphocytic predominance leucocytosis until he was a toddler, which improved again after baricitinib treatment. The persistent mottled reticular skin discolouration noted on the upper and lower limbs slowly improved with time. Future follow-up should include evaluations for diabetes insipidus, insulin-dependent diabetes mellitus, cerebral aneurysms, hypothyroidism, glaucoma and scoliosis.2
Latest two-dimensional echocardiography at toddler age with improvement cardiac function with left ventricular ejection fraction −59%.
Discussion
AGS is a rare inherited leucodystrophy characterised by elevated IFN signalling and immunological upregulation that mimics congenital infections.1 AGS is characterised by microcephaly, developmental delay, hepatosplenomegaly, anaemia, thrombocytopenia, hypertrophic cardiomyopathy and chilblain skin lesions.2 AGS is also characterised by symmetrical cerebral calcifications in the basal ganglia, deep white matter, and frontal and parietal lobes.15 Seven genes have been linked to AGS: DNA exonuclease TREX1 (TREX1), three non-allelic components of RNase H2 endonuclease complex (RNASEH2A, RNASEH2B and RNASEH2C), deoxynucleoside triphosphate triphosphohydrolase SAM domain and HD domain-containing protein (SAMHD1), double-stranded RNA editing enzyme ADAR (ADAR1), and double-stranded RNA cytosolic sensor IFIH1/MDA5 (IFIH1).2 16–18 These genes encode proteins that are implicated either in intracellular nucleic acid accumulation, triggering an innate immune response, or directly involved in IFN signalling pathways.19 No prenatal phenotype has been identified for the detection of AGS. In a recent study of the prenatal phenotype of AGS, four of five fetuses had central nervous system presentations, while the other two showed either pericardial effusion or hydrops fetalis.3 In another case series of 123 cases of AGS, the time at onset and functional assessment results of six infants with cardiomegaly were unavailable.20 AGS is occasionally associated with pulmonary hypertension and cardiac calcification.21 Sanchis et al described a case of non-obstructive cardiomyopathy associated with AGS.22 No genetic screen for the cardiomyopathy phenotype in this case was performed during clinical exome sequencing investigations despite the fact that cardiomyopathy cases with AGS were described. A possible clue to this neonate’s diagnosis could have been his persistent lymphocytic leucocytosis in the peripheral blood observed in the absence of infection. Elevated IFN-α activity and neopterin concentration in the CSF can also support the diagnosis of AGS.2 20 However, a normal CSF cell count can be seen as in our case at an early stage of disease. The presence of many features such as microcephaly, IUGR, cerebral calcifications and hepatosplenomegaly similar to congenital infection in the early postnatal days suggested possible TORCH infection. When TORCH tests were negative, the investigation shifted to genetic causes of TORCH-like syndromes. Clinical exome sequencing which detected homozygous TREX1 gene confirmed the AGS diagnosis. Mendelian mimics of congenital infections are clinically important, especially due to the high risk of recurrence among parents of an affected child. Moreover, understanding genetic disorders masquerading as congenital infections may provide important insight into the pathological processes underlying this recognisable clinical phenotype. Although definitive curative treatment for this condition is lacking, supportive treatment and follow-up are continued. Genetic counselling for parents and older siblings is also suggested.
Learning points
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It is noteworthy that while prenatal tests failed to identify pathology, the diagnosis of Aicardi-Goutières syndrome (AGS) was later confirmed with right phenotypical clues of intracranial calcification along with cardiomyopathy.
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AGS, a congenital infection mimicker, should be considered a differential diagnosis if a neonate has intracranial calcifications, microcephaly and hepatosplenomegaly without TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes and syphilis) infection.
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Although there is no documented prenatal phenotype for AGS, fetal cardiomyopathy or hydrops fetalis may be a manifestation. During the evaluation of prenatal cardiomyopathy cases, an AGS genetic (TREX gene) analysis should be considered.
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Treatment mainly focuses on supportive care in the absence of known prevention or cure; however, in this case, improved neurological, cardiac and pulmonary status of the child was noted after baricitinib therapy.
Ethics statements
Patient consent for publication
Acknowledgments
Dr Nitin Ashok Rewatkar, Radiology Consultant at Rainbow Children’s Hospital, Hyderabad, India; and Dr Radha Rama Devi, Senior Metabolic and Genetics Consultant, Rainbow Children’s Hospital, Hyderabad, India.
Footnotes
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Twitter @DrNKPANIGRAHY
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Contributors NP drafted, edited the case report and treated the patient. SB helped in drafting the case report and helped in treating the patient. LL and DC helped in writing and editing the case report. All authors approved the final draft.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
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