Aicardi–Goutières Syndrome and Type I Interferonopathies

An early-onset monogenic inflammatory encephalopathy mediated by chronic type I interferon activation following failure of self nucleic acid metabolism or sensing; nine genes (AGS1–AGS9) and a spectrum of allelic diseases and related type I interferonopathies.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

Table sources: proportions from GeneReviews and Crow et al. 2015 [2, 6]; transcripts validated as MANE Select [4]; RNU7-1 [15–17]; LSM11 and RNU7-1 [18].

Sources: [8, 19–25]. Leukodystrophy as a general syndrome, autoinflammatory diseases and inborn errors of immunity are not developed; here, non-AGS type I interferonopathies appear as allelic diseases or differential diagnoses.

1. Introduction

1.1. Founding description

In 1984, Jean Aicardi and Françoise Goutières described eight infants from different families with a progressive encephalopathy beginning in the first year of life, characterised by bilateral spasticity, dystonia, acquired microcephaly and rapid neurological deterioration leading to profound disability or death [26]. All had mild but persistent CSF lymphocytosis, and computed tomography (CT) showed variable combinations of bilateral symmetrical basal ganglia calcification, progressive cerebral atrophy and deep white matter hypodensity; calcification and atrophy were present in all families, although not in all patients [26]. The authors recognised the familial and probably genetic nature of the disease and noted that pleocytosis could lead to misdiagnosis as acquired inflammatory disease [26]. Over the following two decades, the resemblance to sequelae of transplacental viral infection led Crow and Livingston to describe AGS as the principal Mendelian mimic of congenital infection [27, 28].

1.2. From the clinical syndrome to the concept of type I interferonopathy

The observation that CSF IFN-α was elevated in these patients without an identifiable infectious agent suggested that the disease resulted from an inappropriately activated innate antiviral response [2]. Gene identification confirmed this hypothesis. In 2006, Crow and colleagues demonstrated that variants in TREX1, the major 3′→5′ DNA exonuclease in mammalian cells, caused the form linked to the AGS1 locus, and that Trex1−/− mice developed inflammatory disease [29]; in the same journal issue, they showed that variants in any of the three ribonuclease H2 subunits (RNASEH2A, RNASEH2B, RNASEH2C) caused recessively inherited AGS with features mimicking congenital viral infection [30]. These were followed by SAMHD1 in 2009, presented as a negative regulator of the cell-intrinsic antiviral response [31], ADAR in 2012, whose deficiency was associated with an ISG signature [32], and gain-of-function IFIH1 variants in 2014, responsible for a spectrum of phenotypes with increased type I interferon signalling [33]. In 2020, Uggenti and colleagues identified, in genetically uncharacterised cases, biallelic LSM11 and RNU7-1 variants, encoding components of the replication-dependent histone pre-mRNA processing complex, and showed that disrupted histone stoichiometry activates cGAS–STING, revealing that nuclear histones help suppress the immunogenicity of self DNA [18].

These discoveries led to application of “type I interferonopathies” to a group of Mendelian disorders in which constitutive activation of the type I interferon pathway causes disease rather than being a consequence [34, 35]. Recent reviews classify these disorders into five mechanistic groups: nucleic acid metabolism and sensing, constitutive activation of innate sensors, proteasome dysfunction, hyperactivation of endosomal Toll-like receptors, and failure of negative regulation of interferon alpha/beta receptor (IFNAR) signalling [36]. AGS is the prototype of the first group, and Inborn Metabolic Diseases includes it among nucleic acid metabolism disorders with an autoinflammatory phenotype, in which poorly processed endogenous nucleic acids are recognised as though viral [34].

1.3. Nomenclature, numbering and reclassifications

Subtype numbering follows OMIM (Online Mendelian Inheritance in Man): AGS1 corresponds to TREX1, AGS2 to RNASEH2B, AGS3 to RNASEH2C, AGS4 to RNASEH2A, AGS5 to SAMHD1, AGS6 to ADAR, AGS7 to IFIH1, AGS8 to LSM11 and AGS9 to RNU7-1 [1–3]. Chapter 39 of Inborn Metabolic Diseases (7th edition, 2022) assigns AGS2 to RNASEH2A, AGS3 to RNASEH2B and AGS4 to RNASEH2C [34]; this order differs from both OMIM and the gene aliases in databases (RNASEH2B with the alias AGS2, RNASEH2C with AGS3, RNASEH2A with AGS4) [3]; OMIM numbering is used, and always giving the gene alongside the subtype number avoids ambiguity.

Several historical designations mostly correspond to AGS. Microcephaly–intracranial calcification syndrome, also called “pseudo-TORCH” or Baraitser–Reardon syndrome, was distinguished from AGS by congenital microcephaly and systemic abnormalities at birth, such as hepatomegaly, elevated liver enzymes and thrombocytopenia; however, these abnormalities occur in patients with confirmed AGS, and most MICS cases had no CSF examination, so most are considered likely to have been AGS [2]. “Pseudo-TORCH” has also been applied to band-like calcification with polymicrogyria due to OCLN variants and to USP18 deficiency, so the term should always be accompanied by the gene [2, 28, 37]. Cree encephalitis, described in children from this indigenous Canadian population, is AGS due to homozygosity for TREX1 p.(Arg164Ter) [2]. The “familial systemic lupus erythematosus” case published by Dale and colleagues in 2000 — two siblings born to consanguineous parents with early encephalopathy, intracranial calcification, chilblains and high-titre autoantibodies — was reinterpreted as AGS [2].

1.4. Definition of the entities within scope

In current practice, AGS is defined as an inflammatory encephalopathy usually beginning in the first months of life, with intracranial calcification, leukoencephalopathy and cerebral atrophy, chronic type I interferon activation, and biallelic or dominant pathogenic variation in one of the nine genes [5, 34]. The 2021 EULAR/ACR (European Alliance of Associations for Rheumatology/American College of Rheumatology) consensus establishes that genetic confirmation is required for an AGS diagnosis [5]. The same genotype may produce phenotypes not fulfilling the classical definition: spastic paraparesis with preserved intellect, isolated bilateral striatal necrosis, isolated chilblains or cutaneous lupus, requiring consideration of a spectrum [6, 35].

Allelic diseases within scope are familial chilblain lupus (TREX1, SAMHD1), RVCL-S (TREX1), dyschromatosis symmetrica hereditaria and interferon-dependent psoriasis due to ADAR loss of function, and Singleton–Merten syndrome type 1 (IFIH1) [2, 19, 24, 25]. Non-AGS type I interferonopathies — SAVI, CANDLE/PRAAS, SPENCD and others — are considered in the differential diagnosis, including the CANDLE/PRAAS mimics, and JAK inhibitor therapy for SAVI is described in 7.3 [5, 20].

1.5. Status of reference sources

The AGS GeneReviews chapter retains the date 22 November 2016, with no subsequent update recorded at the consultation date (10 October 2026) [2]. It remains the reference source for molecular genetics, differential diagnosis and counselling, but does not include LSM11 and RNU7-1, JAK inhibitors, the 2021 EULAR/ACR consensus or subsequent biomarker and natural history studies, which are incorporated from primary literature [5, 6, 38].

The French National Diagnosis and Care Protocol (PNDS) for interferonopathies, published by the Haute Autorité de Santé (HAS) on 6 November 2024 under the coordination of the RAISE reference centre and the FAI²R and BRAIN-TEAM networks, is the most recent national guidance: it treats type I interferonopathies as a group of more than 30 genetic diseases, with AGS as the paradigm, and organises the mechanisms into seven groups — accumulation of endogenous nucleic acids (TREX1, SAMHD1), altered nucleic acid composition (RNASEH2A/B/C, ADAR), increased sensor sensitivity (IFIH1), constitutive activation of an adaptor (STING1), failure of negative regulation (ISG15, USP18, STAT2), failure of regulation of STING trafficking (COPA) and other mechanisms (complement C1q, the Toll-like receptor pathway with TLR7 and UNC93B1, the proteasome, ACP5) [12]. The PNDS does not set JAK inhibitor doses; its recommendations on clinical suspicion, investigations, vaccination, adverse effects, transition and pregnancy are incorporated into the corresponding sections [12].

2. Molecular Genetics and Pathophysiology

2.1. Common mechanism: self nucleic acids recognised as foreign

Cells detect viral nucleic acids through cytosolic sensors. Cytosolic DNA activates cyclic GMP-AMP synthase (cGAS), which produces the second messenger cGAMP; this activates stimulator of interferon genes (STING), which recruits the kinase TBK1 and the transcription factor IRF3, leading to type I interferon production. Double-stranded RNA is detected by the sensor MDA5, encoded by IFIH1, which signals through the MAVS protein to the same pathway [19, 34]. Secreted interferon binds the IFNAR receptor (whose deficiencies have the opposite phenotype) and, through the JAK–STAT pathway, induces hundreds of ISGs, whose expression in blood constitutes the “interferon signature” [34, 39].

In AGS, the defect is upstream: endogenous nucleic acids that should be degraded, edited or correctly packaged accumulate and are recognised as though viral [34]. Variants in any of the genes induce type I interferon production and ISG overexpression resembling responses to viral DNA or RNA, explaining the clinical resemblance to congenital infection [30, 34]. Nucleic acid metabolic steps involving retroelement reverse transcription, SAMHD1, RNase H2 and TREX1 also occur in the nucleus, and altered nuclear cGAS distribution is one proposed mechanism for LSM11 and RNU7-1 [18, 34]. Neuropathology shows diffuse, non-uniform demyelination with astrocytosis, without storage features, wedge-shaped cortical microinfarcts due to microangiopathy, calcium deposits in white matter, thalami, basal ganglia and dentate nuclei, calcification of the media, adventitia and perivascular spaces of small vessels, and leptomeningeal inflammation [2].

2.2. TREX1 (AGS1)

TREX1 (3p21.31; OMIM 606609) is a single-exon gene encoding a 314-amino-acid 3′→5′ exonuclease, anchored to the endoplasmic reticulum membrane by a C-terminal domain of around 75 amino acids [2, 8]. The enzyme degrades single-stranded DNA and mismatched 3′ ends, removes cytosolic DNA derived from endogenous retroelements (L1, LTR, SINE), aberrant replication intermediates and ruptured micronuclei, thereby preventing cGAS–STING activation [8]. Confusion with the overlapping but distinct gene ATRIP is frequent in databases [2].

AGS1 variants abolish or reduce exonuclease activity [24, 29]. Biallelic null variants are frequent in TREX1, unlike RNase H2 genes [6]. The most frequent variant is NM_033629.6:c.341G>A p.(Arg114His), affecting dimerisation, behaving as a functional null and accounting for around 50% of TREX1 alleles in the 2007 cohort; in the 2015 cohort it was present in 35 of 70 TREX1 families, predominantly northern European, and was also found in homozygosity in a Turkish and a Pakistani family [2, 4, 6]. The MANE transcript c./p. numbering matches historical GeneReviews numbering based on sequences AAK07616.1/AF319569.1 [4]. Other recurrent variants are c.490C>T p.(Arg164Ter), a Cree founder variant, and p.(Glu20Glyfs*82), present in 8 South Asian families, 6 homozygous [2, 6]. Dominant inheritance results from specific dominant-negative variants — c.52G>A p.(Asp18Asn), p.(Asp18His) and p.(Asp200Asn) — usually de novo; p.(Asp18Asn) has been transmitted vertically and also causes familial chilblain lupus [2, 4, 6].

C-terminal frameshift variants of TREX1 remove endoplasmic reticulum anchoring but preserve enzymatic activity and cause RVCL-S, an adult small-vessel disease with dominant inheritance [8, 24]. The AGS biochemical profile is not expected in RVCL-S [8]. The possibility that heterozygous parents of a child with AGS1 carrying a C-terminal variant might develop RVCL-S is unproven; the 2015 cohort describes a child with AGS whose mother transmitted p.(Leu287Cysfs*11) (published designation, with no c. description in the source), a C-terminal RVCL-type variant, without the maternal risk being determinable [2, 6]. Heterozygous TREX1 variants were found in 9 of 417 patients with systemic lupus erythematosus (SLE), and OMIM lists TREX1 as an SLE susceptibility locus (MIM 152700), which corresponds to a risk allele rather than a Mendelian diagnosis [2, 8].

2.3. Ribonuclease H2 complex: RNASEH2A (AGS4), RNASEH2B (AGS2) and RNASEH2C (AGS3)

RNase H2 is a heterotrimer comprising catalytic subunit A and structural subunits B and C, and constitutes the main source of RNase H activity in human cells [3]. It degrades the RNA strand in RNA:DNA hybrids, participates in removal of RNA primers from Okazaki fragments and excises single ribonucleotides erroneously incorporated into genomic DNA [2, 3]. Variants in any subunit cause complex loss of function; ribonucleotides accumulate in DNA and endogenous nucleic acid species escape clearance, activating intracellular sensors [3]. Biallelic null RNASEH2A/B/C variants have never been described, suggesting incompatibility with life or a different phenotype [5, 6].

In RNASEH2B (13q14.3; MANE transcript NM_024570.4), almost all variants are missense. Variant c.529G>A p.(Ala177Thr) accounted for 62% of affected alleles in the 2007 cohort and was present in 97 of 107 RNASEH2B families in 2015, across ethnicities, with 48 homozygous families; around 90% of patients with biallelic RNASEH2B variants have at least one p.(Ala177Thr) allele [2, 4, 6]. Other frequent variants are c.488C>T p.(Thr163Ile) and c.554T>G p.(Val185Gly), each accounting for around 7% of alleles, and c.136+1del, accounting for 4% (GeneReviews writes c.136+1delG) [2, 4]. The 2015 cohort also identified intronic variants c.65-13G>A (3 families) and c.322-17A>G (1 family) as likely pathogenic through altered splicing, and a large RNASEH2B deletion [6]. As subunit B is non-catalytic and p.(Ala177Thr) retains partial function, this is considered a possible reason why RNASEH2B occupies the milder, later-onset end of the spectrum, an interpretation that is unproven [3].

In RNASEH2C (11q13.1; NM_032193.4), all described variants are missense; c.205C>T p.(Arg69Trp) accounts for 72% of alleles and was found homozygously in 24 South Asian families, particularly Pakistani, as an ancient founder variant [2, 4, 6]. In RNASEH2A (19p13.13; NM_006397.3), most variants are missense, but splice and frameshift variants occur; synonymous variants c.69G>A p.(Val23=) and c.75C>T p.(Arg25=) are pathogenic through creation of cryptic splice sites and were found in 5 families [2, 4, 6]. A synonymous variant should therefore not be dismissed solely on its predicted protein consequence [3]. GeneReviews and the 2015 cohort use earlier transcript versions (NM_006397.2, NM_024570.3, NM_032193.3) without changes in numbering of the cited variants [4, 6].

2.4. SAMHD1 (AGS5)

SAMHD1 (20q11.23; NM_015474.4) encodes a 626-amino-acid deoxynucleoside triphosphate (dNTP) triphosphohydrolase, with SAM and HD domains, maintaining low dNTP pools, acting as a restriction factor for HIV-1 and LINE-1 retrotransposition, and regulating DNA end resection at stalled replication forks, preventing nucleic acid release into the cytosol [2, 19]. It is expressed in cerebral vessels, proposed as the basis of the arteriopathy characteristic of this genotype [19]. Variants include missense, nonsense, frameshift and splice variants and large deletions, causing protein mislocalisation or loss of function [2]. A recurrent deletion including the promoter and exon 1 (historically designated “8984 bp promoter+ex1del”, without HGVS nomenclature) was found in 10 Ashkenazi Jewish patients, with a carrier frequency of 1/138 in that population according to a conference abstract; as a structural variant, it was not normalised [2, 4, 6]. The splice variant c.1411-2A>G is an Amish founder variant, and p.(Arg145Ter) occurs on an ancestral haplotype shared by 5 families, 4 Maltese [2, 4, 6]. Up to 30% of SAMHD1 alleles in the 2015 cohort (20 of 67) were deletions detectable only by dosage methods [2].

2.5. ADAR (AGS6)

ADAR (1q21.3; NM_001111.5) encodes ADAR1, converting adenosine to inosine in double-stranded RNA, particularly Alu element transcripts; as inosine is read as guanosine, editing alters splicing, stability and microRNA processing and destabilises endogenous double-stranded RNA, marking it as self [19, 32]. Loss of editing allows this RNA to activate MDA5 [19]. The p110 isoform is constitutive and interferon-inducible p150 has an additional 295 N-terminal amino acids with a second Z-DNA-binding domain [2]. Most patients have biallelic variants; c.577C>G p.(Pro193Ala), affecting only p150, was found only in heterozygosity in 13 of 22 ADAR families, predominantly northern European, and occurs in 32 of 4300 European-American alleles [4, 6]. Variant c.3019G>A p.(Gly1007Arg) acts in a dominant-negative manner; it was de novo in almost all cases, but in one family an unaffected father transmitted it to two daughters, demonstrating incomplete penetrance [4, 6, 40]. The same ADAR variant can cause classical AGS, spastic paraparesis or bilateral striatal necrosis [6].

2.6. IFIH1 (AGS7)

IFIH1 (2q24.2; NM_022168.4) encodes MDA5, a cytoplasmic sensor of long double-stranded RNA signalling through MAVS, TBK1/IKKε and IRF3/IRF7 [19]. All AGS-associated variants are heterozygous gain-of-function missense variants causing ligand-independent constitutive signalling [2, 33]. Examples are c.2335C>T p.(Arg779Cys), observed in AGS7, and c.2465G>A p.(Arg822Gln), causing Singleton–Merten syndrome type 1 [4, 19, 41]. Penetrance is incomplete: two carriers with a marked interferon signature were asymptomatic at ages 48 and 79 [6]. Rare loss-of-function IFIH1 variants protect against type 1 diabetes (odds ratio 0.51–0.74), and a recessive loss-of-function form causes immunodeficiency (OMIM 619773); neither constitutes an AGS diagnosis [19].

2.7. LSM11 (AGS8) and RNU7-1 (AGS9)

LSM11 encodes a protein of the Sm core of U7 ribonucleoprotein, and RNU7-1 encodes U7 small nuclear RNA; the complex processes the 3′ end of replication-dependent histone pre-mRNAs [18]. Biallelic variants cause abnormal processing of these transcripts, altered linker histone stoichiometry, redistribution of nuclear cGAS and increased cGAS–STING signalling; in vitro, chromatin lacking linker histone stimulates greater cGAMP production [18]. RNU7-1 variants are predominantly located in the 3′ stem-loop and reduce RNA secondary structure stability [17]. As this is a non-coding gene (NR_023317.1), variants are described using the prefix n.; examples are n.28C>G and n.40_47del in compound heterozygosity and n.28C>A with n.54G>A [4, 16, 41]. In Uggenti and colleagues' original series, 11 patients from 7 families were compound heterozygotes for n.28C>T and a second variant, which was n.40_47del in 3 families [18]; allele n.28C>G, distinct from n.28C>T at the same position, comes from patient P8 in Frémond and colleagues' series [41]. As a small RNA gene, RNU7-1 may escape panels and exomes, and targeted sequencing is recommended in genetically undiagnosed AGS [17]. By 2025, around 19 RNU7-1 cases had been described [16]. The sources consulted do not include individual clinical data for LSM11 patients in full text.

2.8. Normalised variants

All descriptions were validated as MANE Select using the VariantValidator tool (GRCh38) [4]. The SAMHD1 promoter and exon 1 deletion and the RNU7-1 variants n.28C>A and n.54G>A retain the authors' descriptions [2, 16]. A table in a 2023 study gives “p.Ala114His” for the TREX1 variant NM_033629.6:c.341G>A, which corresponds to p.(Arg114His) [4, 41].

2.9. Genotype–phenotype correlations, penetrance and modifiers

The neonatal form resembling congenital infection is more frequent with TREX1, RNASEH2A and RNASEH2C; the later-onset form, sometimes following months of normal development and occasionally with preserved neurological function, predominates with biallelic RNASEH2B, SAMHD1 and ADAR and with dominant variants in ADAR and IFIH1 [2, 6, 42]. In the 2015 cohort, the probability of normal development until onset was 63% with IFIH1, 57% with ADAR and 21% with RNASEH2B, and onset after the first year occurred in 35% of ADAR patients and 30% of IFIH1 patients [6]. SAMHD1 is associated with chilblains, glaucoma, arthropathy and intracranial arteriopathy; ADAR with bilateral striatal necrosis and acute dystonia; and TREX1 with infantile hypertrophic cardiomyopathy [6]. Intrafamilial variability is substantial: an older sister homozygous for RNASEH2C p.(Arg69Trp) had chilblains alone, and a sibling series showed discordant severity in 5 of 13 pairs [6, 43]. Asymptomatic individuals homozygous for RNASEH2B p.(Ala177Thr) have been described [44]. Non-penetrance is documented for ADAR p.(Gly1007Arg) and IFIH1 [6]. The sources consulted identify no validated genetic modifiers.

2.10. Allelic disorders

Sources: [1, 2, 6, 8, 19, 24, 25, 45–47].

The 2026 study of ADAR1-associated psoriasis showed reduced A→I editing and increased ISGs in patients' cells, reversed in vitro by upadacitinib and deucravacitinib; the therapeutic effect in patients was not assessed [25]. Identification of this subtype expands the ADAR spectrum to include cutaneous disease in adolescents and adults without encephalopathy.

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts

The clinical description rests on four types of data. The cohort of Rice and colleagues (2007) included 127 kindreds with a clinical diagnosis and clinical data on 123 patients with variants in TREX1 and the three RNase H2 genes [42]. The international cohort of Crow and colleagues (2015) included 374 patients from 299 families with variants in seven genes, collected non-prospectively through clinical practice and collaborators in the United Kingdom, Italy, the USA and other countries, including centres in Lisbon and Ribeirão Preto [6]. The real-world cohort of the Myelin Disorders Biorepository Project (MDBP) at the Children's Hospital of Philadelphia (CHOP) included 167 patients with genetically confirmed AGS and 129 published cases from 2007 to 2022 with individual-level data [15]. Genotype-specific cohorts, such as the cohort of 42 individuals homozygous for RNASEH2B p.(Ala177Thr), supplement the information [44]. All are referral-centre cohorts, biased towards severe cases and with incomplete follow-up, and primarily describe natural history without targeted treatment.

3.2. Presentations

Around 80% of infants have a normal pregnancy, delivery and neonatal period; cerebral calcifications may nevertheless be identified in utero [2]. In the 2015 cohort, 74 patients (22.8% of those with available data) had prenatal onset: 37 (11.4%) had a congenital infection-like syndrome at birth, with neurological signs, thrombocytopenia and hepatosplenomegaly (25 TREX1, 2 RNASEH2A, 1 RNASEH2B, 3 RNASEH2C, 3 SAMHD1, 1 ADAR and 2 IFIH1), and another 37 (11.4%) had neurological signs at birth without systemic involvement [6]. The neonatal form manifests with irritability, feeding difficulties, tremors, microcephaly, abnormal movements and seizures, with thrombocytopenia, anaemia and hepatic dysfunction that may resolve within weeks; it is associated with severe deficits and greater mortality in the first year [28, 34].

The infantile form is the most frequent: 223 of 325 patients (68.6%) had evident neurological dysfunction in the first year of life [6]. After weeks or months of apparently normal development — normal until onset in 65 children (18.0%) — encephalopathy develops abruptly or subacutely, with extreme irritability, inconsolable crying, sleep disturbance, intermittent sterile fevers, feeding difficulties, loss of acquired skills and slowing of head circumference growth [2, 6, 34]. RNASEH2B is the most frequent genotype in this form [34]. In the MDBP cohort, the median age at systemic onset was 0.15 years and at neurological onset 0.33 years, ranging from zero in TREX1 to 0.62 and 0.90 years in ADAR [15].

The late-onset form, beginning after the first year, occurred in 28 patients (8.6%) in the 2015 cohort; the latest known presentation was subacute dystonia at 5 years in a child with ADAR p.(Gly1007Arg) [6]. The EULAR/ACR consensus reports onset at 5.6 years [5]. In this form, abrupt or subacute neurological regression follows normal development, often with spastic paraparesis; SAMHD1 is associated with a phenotype comprising mild or absent intellectual disability, microcephaly, spastic paraparesis and inflammatory skin manifestations [34].

3.3. Encephalopathic phase and subsequent course

The encephalopathic phase usually lasts several months [2]. Thereafter, most patients do not show continuous deterioration, and some slowly acquire new skills; progression or new episodes of regression occasionally occur, often triggered by infection [2, 6, 41]. Death is attributed mainly to the neurological damage of the initial episode, and several patients aged over 30 years show no signs of progression [2]. CSF IFN-α and neopterin decline over time, while the blood ISG signature persists [6]. Distinguishing this spontaneous stabilisation from the effect of treatment is the principal difficulty in interpreting therapeutic studies [11, 48].

3.4. Neurological manifestations

The predominant signs are peripheral spasticity, dystonic posturing particularly of the upper limbs, axial hypotonia and poor head control [2]. In the MDBP cohort, 145 of 167 patients (86.8%) had axial hypotonia, 123 (73.7%) dystonia and 115 (68.9%) irritability [15]. Seizures occurred in 140 of 362 patients (39%) in the 2015 cohort and are generally relatively easy to control [2, 6]. Cortical blindness occurred in 111 of 362 (31%), sometimes with optic disc pallor [6]. Several children have a marked startle response to sudden noise, which is difficult to distinguish from epileptic seizures [2]. Acquired microcephaly is severe in most, but head circumference is normal in children with preserved intellect, and hearing is almost always normal [2].

Two neurological phenotypes depart from the classical presentation. Thirteen children (3.6%) in the 2015 cohort, all with ADAR variants, had severe acute- or subacute-onset dystonia with bilateral striatal necrosis and no other signs of AGS [6]. Refractory dystonia of all four limbs appears between 8 months and 5 years, sometimes in children with normal development and frequently shortly after an infection; magnetic resonance imaging (MRI) shows symmetrical signal abnormalities in the caudate and putamen, with swelling followed by shrinkage [2, 46, 49]. Twelve patients (3.4%; 6 RNASEH2B, 3 SAMHD1, 2 ADAR, 1 IFIH1) had pure spastic paraparesis with normal or non-specific neuroimaging and preserved intellect [6, 45]. AGS may therefore be misdiagnosed as cerebral palsy or hereditary spastic paraparesis [50].

3.5. Neuroimaging and neuropathology

Calcification, best visualised on CT, involves the basal ganglia — especially the putamen, globus pallidus and thalamus — and extends into the white matter, sometimes with a paraventricular rather than a truly periventricular distribution [2]. It is frequently punctate, may be dense, and when present at diagnosis tends to remain stable; it does not correlate with neurological severity and may be absent, whether or not it appears on repeat imaging [2]. MRI may fail to show extensive calcifications [2, 28]. White matter changes are predominantly frontotemporal, with temporal cysts in severe forms, T2 hyperintensity around the ventricular horns, possibly progressive cerebral atrophy predominantly affecting the anterior temporal lobes, and cerebellar and brainstem atrophy [2, 28, 34]. In the late-onset form with spastic paraparesis, neuroimaging may be normal [34]. Special patterns are bilateral striatal necrosis (ADAR) and intracerebral large-vessel disease with stenoses, aneurysms and haemorrhage (SAMHD1) [34].

3.6. Skin and mucous membranes

Chilblains are erythematous-violaceous lesions induced and exacerbated by cold, affecting the fingers and toes, ears and sometimes pressure points, and are more prominent in winter; periungual infection and necrosis may complicate them [2, 34]. They occurred in 113 patients (31.2%) in the 2015 cohort, across all genotypes, but in 26 of 48 SAMHD1 patients (54.2%) and only one ADAR patient [6]. In the MDBP cohort, they developed in 12 of 50 RNASEH2B patients (24.0%), 12 of 25 SAMHD1, 11 of 26 TREX1 and 2 of 19 IFIH1, with onset between birth and 24.98 years (median 3.01 years); median time to chilblains was 8.53 years in TREX1, 10.65 years in SAMHD1 and 19.39 years in RNASEH2B [15]. Other manifestations include acrocyanosis, periungual erythema, necrotic lesions of the digits and helix, livedo, panniculitis (3 patients in 2015) and recurrent oral ulcers; biopsy may show immunoglobulin and complement deposition in small-vessel walls [2, 5, 6]. Three patients with dominant TREX1 variants had extensive skin involvement, one with severe dactylitis, and psoriasiform lesions occur with IFIH1 [6, 41].

3.7. Eye

Visual function ranges from normal to cortical blindness, and ocular structures are almost always normal [2]. Congenital or late-onset glaucoma occurred in 23 patients (6.3%) in the 2015 cohort, including 10 of 48 with SAMHD1 (20.8%) and none with ADAR or IFIH1; most were diagnosed within the first 6 months of life without glucocorticoid exposure, and one at 6 years [5, 6]. The EULAR/ACR consensus also includes retinopathy among the ocular manifestations [5].

3.8. Intracranial vasculopathy

Intracranial large-vessel disease — stenoses, sometimes with a Moyamoya pattern, aneurysms and early stroke — is almost exclusive to patients with biallelic SAMHD1 variants [2, 6]. In the 2015 cohort, it was confirmed in 9 patients, all with SAMHD1, corresponding to 18% of this genotype [6]. Patients with chilblains appear to be at greater risk [2]. Compound heterozygotes for SAMHD1 with Moyamoya and mitral valve disease without other signs of AGS have been described, so SAMHD1 should be considered in unexplained childhood Moyamoya [19]. In the same cohort, intracerebral haemorrhage occurred at 3 years in a child with TREX1 without a previous vascular abnormality [6].

3.9. Systemic manifestations

The 2007 cohort of 123 patients, preceding the identification of SAMHD1, ADAR and IFIH1, recorded the following infrequent features [2, 42]:

The Italian cohort also described haemolytic anaemia, polygammaglobulinaemia and neonatal cardiomyopathy [51].

The French PNDS adds to the systemic spectrum of AGS and the allelic entities non-destructive arthropathy with Jaccoud-type subluxations, dactylitis, tendon ruptures, acro-osteolysis and widening of the phalangeal medullary cavities on radiography, osteopenia and tendon calcification; dental anomalies (short roots, early loss of permanent teeth, delayed shedding of deciduous teeth requiring extraction, caries); atrophic or autoimmune gastritis; aortic, coronary and valvular calcification and arrhythmias on the electrocardiogram; diabetes insipidus, diabetes, hyperparathyroidism, adrenal insufficiency and GH deficiency; and, as rare or very rare findings, bronchiectasis and interstitial lung disease, recurrent urolithiasis, chronic lymphocytic leukaemia and aggressive T-cell lymphoma, and thrombotic microangiopathy, the latter associated with LSM11 [12]. Precocious puberty is listed among the endocrine manifestations of the group, and AA amyloidosis has been described only in exceptional observations [12].

3.10. Genotype-specific profiles

In the international cohort of 42 individuals homozygous for RNASEH2B p.(Ala177Thr), onset occurred in the first year in 79% (neonatal in 17%, infantile in 62%) and was late in 21%; severity, measured using a composite functional score, was mild in 19%, moderate in 29% and severe in 52% [44]. Initial symptoms were recurrent fever (57%), irritability (45%), sleep disturbance (40%) and feeding difficulties (29%); irritability was absent in all mildly affected patients and present in 58% of moderately affected and 55% of severely affected patients, and neonatal onset was more frequent in severe cases [44]. No single marker was exclusive to the severe group [44].

Among 33 patients with biallelic ADAR1 variants, 79% had severe disability (Gross Motor Function Classification System, GMFCS, level V) or had died [52]. The Belgian RNU7-1 patients had a modest peripheral interferon signature, increased monocyte chemoattractant protein 1 (MCP-1/CCL2) and CXCL10 in CSF, and renal thrombotic microangiopathy; the review of RNU7-1 cases showed high mortality and more frequent organ involvement than in other genotypes [17]. Two siblings with biallelic null SAMHD1 variants illustrate the variability: the older sister had mild intellectual disability and microcephaly, the brother had spastic paraparesis with normal intellect and head circumference, and both had inflammatory dermatosis with chilblains and oral ulcers; one developed progressive deforming arthropathy with contractures [2].

4. Clinical Recognition and Warning Signs

4.1. When to suspect the diagnosis

AGS is a pleomorphic and relatively non-specific group, and most patients first present to paediatric neurology and undergo genetic testing only later [34]. In the MDBP cohort, the median age at first seeking care was 0.34 years and at diagnosis 1.83 years [15]; in families with affected siblings, the older sibling was diagnosed at a median age of 7.32 years and the younger at 1.54 years [43]. Clinical genetics textbooks list AGS in the differential diagnosis of developmental regression (with chilblains and CSF lymphocytosis as clues), dystonia with basal ganglia calcification, progressive microcephaly and CSF lymphocytosis [53–56]. GeneReviews lists encephalopathy and/or significant intellectual disability, acquired microcephaly in the first year, dystonia and spasticity, sterile fevers, hepatosplenomegaly and chilblains of the feet, hands and ears, sometimes with generalised livedo, as suggestive findings [2].

The EULAR/ACR consensus recommends immediate evaluation — genetic testing, extent of organ involvement and screening for comorbidities — in unexplained systemic inflammation, defined by elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and/or an interferon signature, associated with rash, lipodystrophy or musculoskeletal, neurological, pulmonary or metabolic findings (level of evidence 4, grade C) [5]. In AGS, unlike CANDLE and SAVI, CRP and ESR are rarely elevated, so normal values do not rule out the diagnosis [5].

The French PNDS describes three neurological presentations in children: the typical “encephalitic” presentation before 1 year of age, with regression after normal development, aseptic lymphocytic meningoencephalitis persisting for weeks to months and prodromes (developmental stagnation, irritability, sleep disturbance, feeding difficulties, unexplained fever), followed by microcephaly, dystonic-spastic tetraparesis, bradykinesia, dysarthria, axial hypotonia, cognitive impairment, sometimes epilepsy and impaired ocular pursuit; the neonatal or prenatal “pseudo-TORCH” presentation, with hepatosplenomegaly, raised transaminases and thrombocytopenia without an identified virus; and atypical, later-onset presentations — spastic paraparesis, acute or subacute dystonia, ataxia, psychiatric disorder, stroke-like focal deficit, opsoclonus-myoclonus syndrome [12]. A viral illness or a vaccination may precipitate acute decompensation [12]. An interferonopathy should be considered in the presence of aseptic lymphocytic meningitis, isolated or with extraneurological involvement, and of any unexplained neurological picture with cutaneous, pulmonary, gastrointestinal or cardiac involvement; calcifications may be visible on MRI only on susceptibility-weighted sequences (SWI) or only on CT [12]. Interferonopathy chilblains are distinguished from common chilblains by their early onset (first months or years), persistence in summer, atypical locations and necrotic or mutilating course; additional features include necrotising vasculitis of the ears and nose, erythematous and telangiectatic plaques on the cheeks, digital ulcers with atrophic and anetodermic scars, Raynaud phenomenon, livedo, panniculitis with lipodystrophy, lentigines, psoriasis, scleroderma-like lesions, oral ulcers, nail changes and photosensitivity [12].

In the laboratory picture, the PNDS emphasises that the interferon signature is consistently positive, except in 20–25% of RNASEH2B patients and in some asymptomatic COPA carriers; that the inflammatory syndrome is inconstant and moderate, with frequent dissociation between a raised ESR and a normal CRP; that antinuclear antibodies, sometimes ANCA, and rheumatoid factor (even without arthritis) and anti-CCP antibodies are frequent, with anti-DNA antibodies rare outside lupus; that complement is normal, except in monogenic C1q deficiency and in lupus-related consumption; and that T-cell lymphopenia with an excess of naive T cells and a memory cell deficit is characteristic of SAVI and COPA syndrome and inconstant in AGS [12]. The protocol associates lupus or haematological autoimmunity with TREX1, RNASEH2A/B/C, SAMHD1, ADAR, IFIH1, ACP5, C1Q, STING1, COPA, the proteasome genes, TLR7 and UNC93B1; myositis with ACP5, STING1 and the proteasome; non-destructive deforming arthritis and Jaccoud arthropathy with IFIH1, RNU7-1, DDX58, SAMHD1, STING1, TREX1, the proteasome, DNASE2 and COPA; scleroderma-like involvement with ACP5 and ATAD3A; severe interstitial lung disease or alveolar haemorrhage with STING1 and COPA; and thrombotic microangiopathy with LSM11 [12].

Table 4.1a — When to consider a type I interferonopathy in adults (French PNDS, 2024) [12]

4.2. Warning signs and emergencies

During the acute phase, rapid neurological deterioration with uncontrollable irritability, frequent epileptic seizures, acute-onset refractory generalised dystonia, neonatal hyperinflammation partially meeting criteria for haemophagocytic lymphohistiocytosis (HLH), and aspiration constitute emergencies [2, 46, 57]. Throughout life, pulmonary hypertension, cardiomyopathy, glaucoma, diabetes insipidus and stroke due to SAMHD1 arteriopathy require early recognition [5, 6]. During JAK inhibitor treatment, fever, signs of serious infection (including meningitis and pneumococcal sepsis), cytopenias and thrombosis are warning signs [38, 41]. Abrupt withdrawal of these drugs is associated with disease flares [41, 50].

4.3. Newborn screening

There is no newborn screening programme for AGS. In a retrospective study of dried blood spots from 19 children with AGS (six genes; median presentation at 2 months) and 22 healthy newborns, C26:0-lysophosphatidylcholine — a marker used in X-linked adrenoleukodystrophy screening — was above the first-tier threshold (0.4 µM) in 13 of 19 patients (68%), with a median of 0.43 µM, compared with 0.21 µM in controls and 0.72 µM in adrenoleukodystrophy [60]. The interferon signature measured in the blood spot itself was positive in 14 of 19 (sensitivity 73.7%; 95% CI 51–88%), with a specificity of 95% (95% CI 78–99%), including one patient who presented at 36 months; the five negative patients had RNASEH2B variants [60]. The authors emphasise that AGS can cause false-positive results in adrenoleukodystrophy screening, a finding relevant to programmes that already include it [60]. The small sample size precludes estimation of population-level performance.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no validated clinical criteria. GeneReviews defines suggestive clinical, imaging and laboratory findings and two exclusion criteria: evidence of prenatal or perinatal infection (cytomegalovirus, toxoplasmosis, rubella, herpes simplex, Zika, HIV) and evidence of another known metabolic or neurodegenerative disorder [2]. Diagnosis is established by identifying biallelic variants in ADAR, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1 or TREX1, specific dominant heterozygous variants in TREX1 or ADAR, or heterozygous gain-of-function variants in IFIH1 [2], to which biallelic LSM11 and RNU7-1 variants are added [5]. The EULAR/ACR consensus considers genetic confirmation necessary for diagnosing AGS, as it enables targeted treatment, genetic counselling, complication screening and prognostication (overarching principle B; evidence 4, grade C) [5]. The clinical–radiological phenotype with inflammatory CSF establishes the syndrome but does not identify the gene [8].

5.2. Neuroimaging

CT has greater sensitivity for intracranial calcification and is considered the reference standard; MRI is the first modality in most children but may fail to show even extensive calcifications, so consideration of CT is recommended in any child with undiagnosed neurological disease, particularly leukoencephalopathy [28]. Gradient-echo and susceptibility-weighted imaging (SWI) sequences are more sensitive than T1 and T2, although they may not distinguish haemorrhage from calcification [28]. The EULAR/ACR consensus recommends MRI for white and grey matter abnormalities and CT when calcium-sensitive sequences are unavailable or fail to detect calcifications, weighing the risks of sedation (evidence 4, grade C) [5]. Calcifications are more frequent, severe and early in AGS than in CANDLE and rare in SAVI; leukoencephalopathy points towards AGS [5]. In SAMHD1 patients, MR angiography evaluates vasculopathy [5].

5.3. Biomarkers

The interferon signature measures blood ISG expression by quantitative PCR or NanoString technology. In the 2013 case–control study, the 6-gene score (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) corresponded to the median expression ratio relative to controls, with a positivity threshold of 2.466; the median was 12.90 in patients and 0.93 in controls, with 2 of 29 controls positive (7%), and repeat testing was concordant on 39 of 41 occasions [39, 51]. Of the 8 negative patients, 7 had RNASEH2B variants [39]. In the 2015 cohort, 80% of readings were obtained after 4 years, and negativity in RNASEH2B may reflect a faster decline with age [6]. The 2024 validation in 997 samples (334 from AGS), with an independent cohort of 122, identified the median of 4 genes (IFI44L, IFI27, USP18, IFI6) as the best model, with an area under the curve (AUC) of 0.8872 in the training group and 0.9245 in the test group; IFI44L alone had AUCs of 0.8762 and 0.9580 [63]. RNASEH2A and RNASEH2B forms had lower interferon activity and a lower probability of correct classification; intraindividual variability in 358 longitudinal samples supports repeated sampling, and acute infection may transiently increase ISGs [63]. The EULAR/ACR consensus cites a retrospective study with an AUC of 0.98 and sensitivity and specificity above 0.8 for distinguishing interferonopathies from healthy controls and cryopyrin-associated periodic syndrome; there is no internationally standardised methodology or reference range, and the signature is not necessary for diagnosis, may be negative in mild disease or during glucocorticoid treatment, and should be interpreted using the laboratory's values [5]. Thresholds differ between studies (2.466 in the 2013 study, 2.216 in the Italian Pavia cohort and a sum of z-scores of 1.96 in the CHOP programme) [38, 39, 51].

CSF examination is not necessary for diagnosing AGS when genetic confirmation is available, but is useful when the molecular diagnosis has not been established (evidence 4, grade C) [5]. Because of the “temporal trap” — CSF lymphocytosis and IFN-α normalise with age, and the cell count may be normal despite elevated IFN-α — a normal result in an older child does not exclude the disease [2, 3].

The French PNDS distinguishes three methods of investigating the interferon pathway. Interferon activity, the historical technique, measures the ability of serum, plasma or CSF to inhibit the replication of vesicular stomatitis virus in culture [12]. The interferon signature quantifies ISG transcripts such as IFI27, IFI44L, IFIT1, ISG15, RSAD2 and SIGLEC1 in whole blood by RT-qPCR or molecular hybridisation; it is not specific, has a negative predictive value of 95%, and two negative samples taken at different times in principle exclude a genetic interferonopathy, with the exceptions of some RNASEH2 patients and asymptomatic COPA carriers; the sample is collected in a PAXgene RNA tube, stable for 72 hours at room temperature and for several months frozen, and in France the test is performed routinely in the immunology laboratory of the Hôpital Lyon Sud, the reference laboratory [12]. Measurement of IFN-α protein by single molecule array (Simoa) in serum, plasma or CSF is highly sensitive, but depends on the antibody and the analyser, requires rapid transport or immediate freezing because of the lability of the protein, and remains reserved for research [12]. In all cases, confirmation is by genetic sequencing [12].

5.4. Genetic testing

The consensus recommends next-generation sequencing — a panel, exome or genome — rather than gene-by-gene Sanger sequencing, which is reserved for known familial variants [5]. The panel should include TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, IFIH1, LSM11 and RNU7-1 (evidence 4, grade C) and, ideally, differential diagnosis genes [2, 5]. GeneReviews also describes an ethnicity-guided sequential gene-testing strategy, now superseded by panels [2].

Source: [2]. Sequencing coding and splice regions of the seven classical genes identified variants in approximately 90–95% of patients with typical clinical presentation and MRI; this is the proportion of molecularly diagnosed cases in selected cohorts, not the test's clinical sensitivity [2]. In the Italian cohort, 48 of 51 patients had identified variants [51].

Technical limitations are concrete. Large deletions, such as the recurrent SAMHD1 deletion, may escape exome sequencing and require dosage analysis (MLPA or validated CNV analysis) [5, 6]; a homozygous deletion may manifest only as amplification failure [2]. If only one variant is found in RNASEH2A/B/C or SAMHD1, or a heterozygous TREX1 or ADAR variant not known to be dominant, a second alteration should be sought by deletion and duplication analysis and review of deep intronic and synonymous variants affecting splicing [2, 6]. In the 2015 cohort, four children with a convincing clinical diagnosis had only one recessive variant, always inherited from an unaffected parent [6]. RNU7-1 is a small non-coding RNA gene that may not be covered by panels and exomes [17]. Mosaicism is not documented in AGS in the sources consulted, but a negative test does not exclude diagnosis; the consensus recommends referring patients with a compatible phenotype without an identified variant to research centres (evidence 5, grade D) [5]. The 2026 preprint on PTPN1 suggests that some undiagnosed patients may have variants in this gene, a finding not yet peer reviewed [64].

The report should state the gene, MANE transcript and version, HGVS c. and p. nomenclature (or n. for RNU7-1), zygosity, variant phase when known and classification according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, under which pathogenic and likely pathogenic classes are clinically equivalent [2]. A variant of uncertain significance (VUS) neither confirms nor excludes diagnosis; parental testing (cis/trans phase and de novo occurrence) and the interferon signature may help reclassify it [2, 8]. Three patients in the 2015 cohort had three deleterious variants in two genes, of uncertain significance [6]. DNA from probands without a molecular diagnosis should be stored [2, 28].

The French PNDS indicates sequencing of the interferonopathy genes for an early-onset presentation or a familial form, with consanguinity and severity as additional arguments; sequencing targeted to a single gene or hotspot (TREX1, COPA, STING1) is no longer recommended and has been replaced by NGS panels and genome-wide analyses (exome, genome) [12]. A negative panel does not exclude monogenic or digenic disease and justifies exome or genome sequencing after assessment in a specialist centre, and the regular discovery of new genes justifies periodic reassessment of the genetic diagnosis; at the time of the protocol, no late-onset somatic variant had been described, although the authors acknowledge that mosaic forms may come to be reported [12].

5.5. Additional assessment after diagnosis

The consensus recommends screening for comorbidities in all systems (skin, nervous system, lung, liver, metabolism and endocrine system, musculoskeletal system, growth and development, blood, eye and heart) (evidence 4, grade C), a basic immunodeficiency investigation with infection history, lymphocyte subsets and immunoglobulins (evidence 4, grade C) and, before starting JAK inhibitors, renal ultrasound and a urinary protein/creatinine or albumin/creatinine ratio [5]. GeneReviews adds developmental, feeding and nutritional assessment, ophthalmological examination, electroencephalogram (EEG) if seizures are suspected and genetics consultation [2].

The French PNDS guides the initial assessment according to the organs involved: full blood count, ESR, CRP, transaminases, electrolytes, creatinine and urea, calcium, phosphate, 25-hydroxyvitamin D, total protein, proteinuria, creatine kinase and thyroid function; antinuclear antibodies and, as appropriate, anti-DNA antibodies, rheumatoid factor, anti-CCP, antiphospholipid antibodies and ANCA; lymphocyte immunophenotyping, because CD4 lymphopenia justifies prevention of opportunistic infections; pulmonary function tests with DLCO and KCO, daytime or nocturnal oximetry, a walk test, chest radiography and CT in lung involvement (especially SAVI and COPA syndrome); echocardiography with estimation of pulmonary pressures and imaging of the vascular axes; orthopantomography or dental CT; joint radiography and ultrasound and muscle MRI; brain and spinal MRI, sometimes brain CT, electromyography with nerve conduction studies and somatosensory evoked potentials if there are neurological signs; and an ophthalmology consultation with visual acuity, slit-lamp examination, fundoscopy and regular measurement of intraocular pressure [12]. There is no standardised severity scale for the interferonopathies as a whole; there are a developmental scale and a clinical scale for AGS (Adang and colleagues, 2020) and a clinical score used in the first SAVI trials, and severity is assessed by functional, anatomical and histological criteria and by the interferon signature [12].

5.6. Algorithm

5.7. Prenatal and preimplantation diagnosis

After identification of familial variants, molecular prenatal diagnosis and preimplantation genetic testing (PGT) are possible [2]. Observations of cerebral calcifications in utero and elevated fetal blood IFN-α at 26 weeks are historical findings from isolated cases rather than validated prenatal tests; normal ultrasound does not exclude disease in an at-risk pregnancy [2].

6. Differential Diagnosis

6.1. Intracranial calcification with early encephalopathy

Basal ganglia calcification is non-specific, and the AGS differential includes infections, other genetic diseases with calcification and leukoencephalopathies [2, 28].

Sources: [2, 5, 12, 28, 34, 37, 49, 58, 65].

Congenital infections are the most frequent differential and the most important to exclude, because an incorrect infection diagnosis leads to underestimation of the 25% recurrence risk in a recessive disease [2]. Cytomegalovirus causes mainly periventricular calcifications and is the most common cause of calcification associated with polymicrogyria [28, 65]. Fetal brain disruption sequence, described in congenital Zika, may have recessive genetic phenocopies, including AGS and “pseudo-TORCH” forms [65]. Physical examination guides diagnosis: chorioretinopathy and deafness suggest infection, retinal telangiectasia suggests Coats plus, cataract or microphthalmia suggest COL4A1, photosensitivity suggests Cockayne, dyskeratosis suggests a telomere disorder, osteoporosis suggests CTC1 and chilblains suggest AGS [28]. Three patients described by Blau and colleagues in 2003, with very elevated neopterin and biopterin and low CSF 5-methyltetrahydrofolate, without lymphocytosis or elevated IFN-α, constitute an undefined syndrome; a similar pterin profile was observed in confirmed AGS [2].

The French PNDS adds practical details to the differential diagnosis: distinguishing AGS from cytomegalovirus fetopathy can be very difficult, and direct testing for the virus on the Guthrie card, stored for at most 2 to 3 years, helps especially if there is deafness, whereas a negative result or the absence of anti-cytomegalovirus antibodies supports molecular testing [12]. In an encephalitic presentation, brain imaging is the key to separating an infectious or post-infectious encephalitis, and calcifications, cysts and haemosiderin deposits (microhaemorrhages) help in the discussion; lymphocytic meningitis requires exclusion of viral infection and, more rarely, haemophagocytic lymphohistiocytosis with purely neurological forms; organomegaly requires exclusion of lysosomal storage diseases; and the early onset and severity of spasticity or dystonia point to an interferonopathy in spastic diplegias [12]. Interferon markers may be absent or equivocal in the sequelae phase or in certain genetic forms, and exome or genome sequencing identifies atypical or borderline forms [12]. Outside neurology, juvenile lupus and juvenile dermatomyositis mimic the interferonopathies, some monogenic lupus forms (ACP5, C1Q, TREX1, UNC93B1) are themselves interferonopathies, acral lesions and nasal septal perforation mimic ANCA vasculitis, the interstitial lung disease of anti-MDA5 dermatomyositis mimics that of SAVI and COPA syndrome, and alveolar haemorrhage requires exclusion of infections, connective tissue diseases, sarcoidosis, vasculitis, alveolar proteinosis, surfactant protein deficiencies and toxic causes; in recurrent fever, the inflammasomopathies have no interferon signature outside viral infection, but DADA2 and other rare autoinflammatory diseases may have one [12].

6.2. Other type I interferonopathies

The EULAR/ACR consensus identifies genetic mimics of CANDLE, SAVI and AGS and partially overlapping entities [5]. The distinction depends on the pattern of organ involvement, inflammatory markers and gene; JAK inhibitor therapy, common to all three, is described in 7.3.

Sources: [5, 8, 19, 20, 24, 34, 37, 59, 64, 66, 67].

CANDLE and SAVI share a chronic interferon signature with AGS but differ in systemic inflammation: CRP and ESR are typically elevated in these two diseases and rarely in AGS [5]. In CANDLE, daily fever, frequently below 38.3 °C in a mildly ill child, skin plaques leaving purpuric macules, histology with an immature myeloid cell infiltrate, panniculitis and lipodystrophy of the face and upper body established before puberty are characteristic; there is chronic microcytic anaemia, thrombocytosis, elevated transaminases and triglycerides and inflammatory organ attacks (epididymitis, conjunctivitis, episcleritis, parotitis, pneumonitis, nephritis, carditis) that may be fatal [20]. The PSMB8 variant NM_148919.4:c.224C>T p.(Thr75Met) is recurrent in Portuguese, Mexican and other patients as a mutational hotspot rather than a single founder haplotype; the form described as joint contractures, muscular atrophy, microcytic anaemia and panniculitis-induced lipodystrophy syndrome (JMP) was reported in three adults from families in Portugal and Mexico [20]. Recessive RNASEH2A/B/C variants appear among CANDLE mimics in the consensus, and TREX1 variants among SAVI mimics, showing the overlap between the three presentations [5].

SPENCD presents, with variable expressivity even between siblings, with short stature, vertebral and metaphyseal changes, autoimmunity and cerebral calcifications with spasticity; in a survey of 26 patients from 18 families, 22 had autoimmune disease, mainly autoimmune thrombocytopenia and SLE, and approximately half had rising IgG, with smouldering myeloma described [20, 66, 67]. Skeletal abnormalities may be absent and the interferon signature is not universal [20]. Radiology shows platyspondyly, sometimes with nodular lesions in the dorsal third of vertebral bodies, and mild enchondromas at the knee, wrist or iliac crest, which may be mistaken for rickets; radiological severity does not correlate with immune or neurological disease [66, 68].

Familial chilblain lupus and RVCL-S are TREX1 allelic diseases (section 2.10) that should be distinguished from AGS in counselling: the first is a cutaneous disease with an interferon signature, and the second an adult small-vessel disease in which exonuclease activity is preserved and the AGS CSF profile is not expected [8, 24]. In RVCL-S, intravenous tissue plasminogen activator should be avoided in acute ischaemic stroke without evidence of large-vessel occlusion [8, 24].

The French PNDS classifies COPA syndrome as an interferonopathy, because the COPA protein regulates STING trafficking, and compares it with SAVI [12]. SAVI, described in 2014 and caused by activating STING1 variants, counts about a hundred published patients; fibrosing interstitial lung disease is the main cause of morbidity and mortality, may be insidious and is assessed by chest CT, pulmonary function tests with volumes and DLCO, the 6-minute walk test and daytime and nocturnal oximetry, with bronchoalveolar lavage and lung biopsy in severe cases; cutaneous vasculopathy may lead to tissue loss and nasal septal perforation, and the poor response to conventional immunosuppressants explains the childhood mortality [12]. In COPA syndrome, described in 2015, heterozygous variants cause recurrent alveolar haemorrhage or interstitial lung disease, arthritis and glomerulopathy; the interferon signature is positive in all symptomatic patients, but may be negative in healthy carriers; osteonecrosis and severe erosive bone lesions have been documented, and JAK1/2 inhibitors improved pulmonary or joint signs in several patients [12]. Autoantibodies, mainly antinuclear antibodies and ANCA without specificity, are present in more than 80% of patients with either disease, and a positive rheumatoid factor is an orienting feature in children [12].

Table 6.2b — SAVI and COPA syndrome according to the French PNDS (2024) [12]

Table 6.2a — Other genetic interferonopathies listed in the French PNDS and not included above [12]

7. Treatments and Risk Management Strategies

7.1. Principles and objectives

The 2021 EULAR/ACR consensus is the only specific international guidance and resulted from a systematic literature review up to September 2020, two Delphi rounds and consensus meetings; AGS statements were voted on by 14 experts, one allied health professional and one patient representative, with acceptance at 80%; it was published simultaneously in Annals of the Rheumatic Diseases and Arthritis & Rheumatology [5, 69]. It establishes four general principles: interferonopathies cause chronic systemic and organ inflammation that, untreated, leads to progressive damage and increased mortality (evidence 4, grade C); genetic confirmation is necessary (4C); treatment aims to reduce systemic and organ inflammation, prevent or limit damage and improve quality of life (2B); and activity, damage and complication monitoring should be undertaken long-term by a multidisciplinary team (4C) [5]. The target is disease control or low activity (2B) [5]. Since established neurological damage is irreversible, the consensus prioritises early treatment [5, 8]. Most patients develop disease after birth, defining a potential therapeutic window [6].

The French PNDS starts from the same principle: there is no curative treatment, the goals are to control systemic and organ inflammation — difficult when it affects the CNS —, to prevent or halt damage and to treat symptoms, and diagnosis and intervention should be early [12]. The indication for disease-modifying treatment, especially a biological therapy, is not systematic, requires discussion at a multidisciplinary team meeting with a benefit–risk assessment and is directed essentially at extraneurological inflammatory manifestations [12].

The 2016 GeneReviews, predating JAK inhibitors, confines itself to supportive treatment and states that the role of immunosuppression was under investigation [2]. Inborn Metabolic Diseases (2022) describes options as mainly symptomatic and targeted approaches as exploratory, and one of its tables lists baricitinib as AGS “emergency treatment”, without a dose or primary source [34, 59]. A 2020 review of AGS treatments identified, besides JAK inhibitors and antiretrovirals, anti-interferon antibodies, anti-type I interferon receptor antibodies and molecules targeting other pathway components as investigational targets [34, 70]. These differences reflect source dates rather than fundamental disagreements.

7.2. Supportive treatment and rehabilitation

Supportive treatment remains the foundation for all patients. It includes respiratory physiotherapy and prompt treatment of respiratory complications, which are a major cause of morbidity and death; attention to diet and feeding route, with adequate caloric intake and prevention of aspiration; and treatment of seizures according to usual protocols [2, 3]. In the MDBP cohort, 43.1% of patients required a feeding tube or gastrostomy, a need associated with greater neurological severity [15]. The consensus recommends a multidisciplinary team (evidence 5, grade D), regular monitoring with validated scales, patient-reported outcomes and quality of life (5D), growth and development assessment at each visit (5D), family education on skin care, physiotherapy, home stretching, positioning, sleep–wake rhythm disturbance and irritability, surveillance for hip dislocation and scoliosis in non-ambulant patients and access to assistive devices [5]. In one published case, trihexyphenidyl, levetiracetam and topiramate were used for dystonia [71]. The French PNDS describes the neurological management of AGS as that of a person with profound multiple disabilities, referring to the generic PNDS for polyhandicap: about 30–50% of children develop epilepsy, usually drug-responsive, treated with conventional antiepileptic drugs preferably as monotherapy (sodium valproate, carbamazepine, lamotrigine, levetiracetam, benzodiazepines), sometimes as polytherapy; disabling or painful dystonic crises may improve with trihexyphenidyl, levodopa, gabapentin, amitriptyline, benzodiazepines or clonidine, introduced at progressively increasing doses over weeks after specialist advice; for spasticity, oral baclofen or botulinum toxin injections, usually every 6 months, are the options, bearing in mind that baclofen may worsen axial hypotonia and occasionally cause a comatose state requiring dose reduction or discontinuation [12]. For sialorrhoea, the protocol proposes a quarter to one transdermal hyoscine (scopolamine) patch behind the ear, changed every 72 hours, or botulinum toxin into the salivary glands; for nociceptive or neuropathic pain, gabapentin, pregabalin, amitriptyline or carbamazepine [12]. Feeding requires adaptation of positioning, textures and caloric intake, with gastrostomy in case of persistent difficulties or aspiration; weight loss linked to cellular stress of the white matter, triggered by surgery, infection or psychological stress, may also require enteral nutrition [12]. In advanced scoliosis, spinal arthrodesis or instrumentation may be proposed, surgery for hip dislocation, and surgery for tendon retractions resistant to medical treatment and botulinum toxin, after multidisciplinary assessment of the general condition; rehabilitation (physiotherapy, psychomotor therapy, speech and language therapy, occupational therapy) and assistive devices (moulded seating, wheelchairs, orthoses, moulded mattress, standing frame, braces) are coordinated by medico-social services, and the application to the departmental centre for disabled persons (maison départementale des personnes handicapées, MDPH) gives access to recognition of disability and to benefits [12]. Chilblains benefit from protection against cold and damp [8]. Glaucoma is treated surgically when congenital, as in the case in section 10, treated with trabeculotomy [57].

Occlusive or aneurysmal SAMHD1 arteriopathy is potentially treatable by revascularisation, embolisation or clipping [2]. Its probably inflammatory basis suggests a role for immunosuppression, but no evidence permits a recommendation, and whether inflammation is active at presentation or the lesion results from an already quiescent process remains unclear [2].

For skin lesions, the French PNDS recommends protection against cold (avoidance when possible, protection of the face and extremities, gloves, layered thermal clothing, heaters and heated gloves) and against microtrauma, sometimes with workplace adaptation; hydroxychloroquine may be proposed with modest results, potent topical corticosteroids help in painful non-ulcerated pseudo-chilblains, and compounded topical ruxolitinib preparations may be used in refractory forms in a specialist centre [12]. Ulcers and necrosis require local care, investigation for osteitis when there is bone contact and adaptation of antibiotics and surgery to local samples; JAK inhibitors may be discussed for ulcers and tissue loss [12].

7.3. Janus kinase inhibitors

Mechanism and rationale. Baricitinib and ruxolitinib inhibit JAK1 and JAK2, and tofacitinib inhibits JAK1 and JAK3; by blocking signalling downstream of IFNAR, they reduce ISG expression [5, 38, 72]. The EULAR/ACR consensus considers JAK inhibitors beneficial for CANDLE/PRAAS, SAVI and AGS symptoms (evidence 2B; agreement level 9.3 out of 10), with baricitinib the most widely used [5]. In AGS, studies describe reduced ISG scores and improvement in neurological disability, crying, sleep disturbance, irritability, seizures, fever and skin inflammation [5]. No JAK inhibitor is authorised for AGS in the USA or EU, and all use is off-label [9, 10, 73, 74].

Evidence. In the open-label, single-centre CHOP expanded-access programme, 35 genetically confirmed AGS patients received baricitinib for at least 12 months; median age at initiation was 2.9 years (0.2–21.8) [38]. The parental diary severity score improved at 1 month (−0.7; 95% CI −1.2 to −0.2) and sustainably (−1.4; 95% CI −2.2 to −0.6); the proportion with a skin subscore of 0–1 increased from 66% to 83% [38]. Before treatment, 26 of 35 patients were stable or declining; during the study, 20 reached new developmental milestones and 12 gained 2 to 7 skills, with a mean gain of 1.3 milestones (95% CI 0.6–1.9), greater in the highest dose category [38]. The subsequent single-arm phase 2 trial (NCT03921554) included 54 patients aged at least 1 month and weighing at least 4.5 kg; the AGS severity scale (0 to 11) increased from a baseline mean of 4.8 to 5.9 at 52 weeks (change +0.9; 95% CI 0.5–1.2), and the ISG score fell 8.76 points at 3 days [75]. Gross motor function (GMFM-88) improved only in the intermediate-severity group (+7.0; 95% CI 1.9–12.0), without change in the most severe and mildest groups [75].

In the Necker Hospital (Paris) real-world study, 11 patients received ruxolitinib or baricitinib, with median follow-up of 17 months [41]. Extraneurological manifestations responded: chilblain improvement, remission of psoriasiform lesions, remission of autoimmune haemolytic anaemia and steroid-dependent immune thrombocytopenia allowing corticosteroid discontinuation, control of erythromelalgia and complete weaning from enteral feeding in 3 of 4 patients [41]. The neurological severity scale improved little (mean +1.2 points), mainly in smiling and vocalisation, without changes in dystonia, communication or caregiver scales [41]. One RNASEH2B patient treated preventively at 5 months developed neurological disease at 15 months, and one ADAR1 patient had an exacerbation with new inflammatory lesions and cavitation on MRI despite normalisation of the blood interferon score [41]. CSF baricitinib concentration was 10–20% of blood concentration and ruxolitinib approximately 10%, proposed by the authors as a likely explanation for the limited neurological response [41]. In the Italian retrospective study, 12 patients treated with baricitinib or ruxolitinib were compared with 20 untreated patients: there was immunological and dermatological benefit, neurological effects were limited and heterogeneous, greater in mild or intermediate phenotypes and with early initiation, and untreated patients had equal or greater neuroradiological improvement [11].

A Boston series of 7 children with movement disorders treated with baricitinib (2–8 mg/day in divided doses, weight-adjusted) and, in 3, anifrolumab recorded interferon signature normalisation in 6 and stabilisation or improvement without new regression episodes in 6, with variable motor outcomes [50]. An Australian series showed a median 81.5% reduction in CSF neopterin in 5 patients treated with JAK inhibitors versus 7% in 8 untreated patients [61]. In a German study, plasma NfL fell from 10.32 to 7.28 pg/mL in 11 patients on JAK inhibitors, without an interferon score change [62]. In AGS7/Singleton–Merten overlap, tofacitinib improved psoriatic and ulcerative lesions without reducing ISGs [72]. The Japanese phase 2/3 study included only one or two AGS patients, without diary improvement, and was terminated for efficacy reasons [76, 77]. An RNU7-1 case had only transient skin and stomatitis improvement, without hepatic or neurological effects, and the drug was discontinued because of nausea and headaches [16]. The EMA, assessing 39 AGS patients among 71 paediatric patients with interferonopathies and juvenile dermatomyositis treated with up to 12 mg/day, concluded that methodological deficiencies precluded efficacy conclusions, and recorded three deaths in the AGS population of uncertain relationship to treatment [10].

Published doses (off-label). The EULAR/ACR consensus does not set doses in the main text and compiles the published JAK inhibitor doses in supplementary table 4 [5]; the doses below come from published studies and cases. Paediatric baricitinib pharmacokinetics involve a substantially shorter half-life than in adults, which justifies more frequent dosing and doses adjusted to weight and estimated glomerular filtration rate (eGFR) [5]. The exposure obtained in AGS (median AUC0–24 1332 ng·h/mL) exceeded that of recommended rheumatological doses (562 ng·h/mL) [41], and the doses used in interferonopathies are much higher than those used in rheumatoid arthritis [78].

Safety and monitoring. Two patients died in the expanded-access programme — one on glucocorticoids for a decade with AGS-related multiorgan failure and opportunistic infection, and another with pulmonary hypertension and thrombotic microangiopathy — and thrombocytosis was the only laboratory variable increasing in severity [38]. In the phase 2 trial there were 3 deaths in 54 patients and serious adverse events in 33 of 51, mainly seizures (11), encephalopathy (8), lung infection (8), fever, anaemia, neutropenia and respiratory failure, with one bilateral pulmonary embolism, one aspergillosis and one meningitis case; among non-serious events, BK viruria occurred in 15 and viraemia in 8 [75]. In the Necker Hospital study, 7 of 11 patients had adverse events: cytopenias in 3, serious bacterial infections in 4, all on baricitinib (osteomyelitis, pneumococcal sepsis and meningitis, aspiration pneumonia, pyelonephritis), and excessive weight gain with ruxolitinib in 3; both pneumococcal infections occurred in children under 2 years with complete 13-valent conjugate vaccination, due to non-vaccine serotypes [41]. In the Boston series, thrombocytosis (2 of 7), anaemia (3), hyperlipidaemia (2), elevated creatine kinase (4) and weight gain (2) limited treatment in 3 patients [50].

The consensus recommends, on JAK inhibitors, comorbidity screening and BK polyomavirus viral load monitoring in urine and blood before initiation and at every visit (evidence 5, grade D); antiviral prophylaxis is not routinely recommended; and thrombocytosis, leucopenia and infection should be monitored particularly in patients with thrombotic risk factors or receiving systemic glucocorticoids or other immunosuppressants [5]. Monitoring at each visit includes differential blood count, liver tests, urinalysis, renal function or creatinine clearance, urine and blood BK viral load and urinary β2-microglobulin [5]. Treating centres describe prior Epstein–Barr virus, cytomegalovirus and herpesvirus 6 PCR testing and hepatitis B and C, herpes simplex, HIV and tuberculosis serology [50]. The baricitinib label requires tuberculosis and viral hepatitis screening, blood count and hepatic and renal function before initiation, and does not recommend starting or maintaining the drug with lymphocytes below 500/µL, neutrophils below 1000/µL or haemoglobin below 8 g/dL [9]. The US label boxed warning includes serious infections, mortality, malignancy, major cardiovascular events and thrombosis [9]. Baricitinib is not recommended with eGFR below 30 mL/min or severe hepatic impairment, and strong OAT3 transporter inhibitors such as probenecid require dose reduction [9, 10]. Ruxolitinib requires a blood count before initiation and every 2–4 weeks until a stable dose, a lipid profile 8–12 weeks after initiation and tuberculosis, herpes and hepatitis B testing [73].

Duration and discontinuation. Required duration is undefined; one centre considers treatment lifelong because abrupt discontinuation was associated with neurological worsening, and recommends gradual reductions with interferon signature monitoring [50]. The consensus warns of withdrawal flares, and the French study of a cytokine crisis after overly rapid discontinuation [5, 41]. The ruxolitinib label describes symptom exacerbation after interruption and recommends gradual tapering [73].

Patient selection. There are no validated criteria. In the French study, untreated patients had severe fixed brain damage without CSF inflammation, cardiomyopathy, minimal cutaneous vasculopathy without neurological disease or parental refusal; treatment indications were systemic manifestations, episodic neurological regression, discomfort and, in one case, presymptomatic prevention [41]. Available data suggest greater benefit when treatment starts in the active inflammatory phase and in less severe phenotypes [11, 75, 80].

Position of the French PNDS (2024). The protocol lists the oral JAK inhibitors available in France — baricitinib and ruxolitinib (JAK1/JAK2), tofacitinib (JAK1/JAK3), upadacitinib and filgotinib (JAK1-selective) and deucravacitinib (TYK2-selective) —, none with a marketing authorisation in the interferonopathies, and stresses that none has been studied in randomised trials, that long-term data are scarce and that the indication should be discussed at a multidisciplinary meeting in a specialist centre, with patients enrolled in registries [12]. Baricitinib is the most widely used, the effective doses in the interferonopathies are higher than those recommended in adult rheumatoid arthritis, and there are no paediatric or interferonopathy data for upadacitinib, filgotinib or deucravacitinib [12]. Benefit–risk data relate mainly to PRAAS and SAVI: in PRAAS, an open-label study achieved complete clinical and laboratory remission with corticosteroid withdrawal in 50% of patients; in SAVI, the benefit is usually incomplete (fewer vascular and febrile flares, prevention of skin involvement, stabilisation of interstitial lung disease with preservation of lung function), no patient achieved complete remission and treatment should start before irreversible lung damage; in AGS, the place of these drugs is not defined and the long-term benefit on development and neurological symptoms is considered uncertain and very guarded, with possible value for extraneurological manifestations such as chilblain lupus, mainly because of the early onset of inflammation in the developing CNS and poor blood–brain barrier penetration [12]. Corticosteroids are useful in CANDLE/PRAAS and in SAVI/COPA with systemic inflammation, at the lowest effective dose [12].

Regarding safety, the PNDS considers infections the dominant adverse effect in children, aggravated by doses higher than those on the label: varicella-zoster virus reactivations (shingles) are the most frequent, but the data do not justify systematic antiviral prophylaxis in PRAAS and SAVI, and it is not recommended in AGS [12]. In a child with no history of varicella, vaccination may be discussed if there is no contraindication, postponing the JAK inhibitor by one month; in a seronegative patient on treatment, short prophylaxis after exposure is recommended, started by day 7 and continued for 15 days, and, depending on the degree of immunosuppression, specific anti-VZV immunoglobulin (Varitect®) within the following 96 hours; varicella or shingles are treated orally or intravenously according to severity [12]. BK polyomavirus reactivation can cause interstitial nephritis in the native kidney with no available treatment, so BK viral load in blood and renal function are measured before starting, at initiation and regularly thereafter [12]. Severe infections with encapsulated bacteria (pneumococcus, meningococcus) and, very rarely, opportunistic infections (toxoplasmosis, JC virus, tuberculosis, atypical mycobacteria, aspergillosis) have been observed; the dose-dependent haematological toxicity of JAK2 inhibitors, through blockade of erythropoietin and thrombopoietin, and hepatotoxicity justify laboratory tests before and during treatment; thromboembolic risk should be weighed against other factors (antiphospholipid antibodies, immobility, age), although only exceptional events have been observed in the interferonopathies; lipids change and excessive weight gain may occur, possibly through inhibition of leptin signalling via JAK2 [12]. Growth, puberty, bone metabolism and infectious and thrombotic complications should be monitored, and the PNDS cites the ORAL Surveillance trial — more than 4,000 patients with rheumatoid arthritis aged over 50 years with at least one cardiovascular risk factor, with an increase in cancer and major adverse cardiovascular events on tofacitinib compared with anti-TNF agents — as a reason for longitudinal studies in children [12]. Most JAK inhibitors are metabolised by cytochrome P450, whereas baricitinib is eliminated mainly by the renal route, and transporter interactions should be reviewed before each prescription; the dose may be adjusted according to response and pharmacokinetics, when available, in consultation with the centre [12]. Treatment should not be stopped abruptly, because of the risk of a hyperinflammatory state and sudden relapse; any discontinuation should be planned, very gradual, under close monitoring and possibly with corticosteroids; a mild infection does not justify discontinuation, and in severe infection the adjustment is decided with the centre [12].

Before starting a JAK1/2 inhibitor, the PNDS requires serology for HIV, hepatitis B and C and VZV (if there is no history of varicella), blood BK virus PCR, an interferon-gamma release assay (Quantiféron®) for latent tuberculosis, a full lipid profile and a full blood count with reticulocytes and platelets, and targeted investigation of any infectious focus [12].

7.4. Glucocorticoids and other immunomodulators

Chronic glucocorticoids do not improve AGS neurological manifestations; short courses may help acute inflammatory manifestations in and outside the central nervous system (CNS), such as cytopenias and hepatitis (evidence 5, grade D) [5]. Corticosteroids may lower CSF interferon without demonstrated clinical benefit [2]. In the neonatal case in section 10, intravenous dexamethasone (2 mg/kg/day) and intravenous immunoglobulin (1 g/kg twice weekly) were used for suspected viral HLH, and methylprednisolone (2 mg/kg/day) perioperatively [57]. In an ADAR1 infant, oral dexamethasone pulses (20 mg/m² for 3 days every 3 weeks) combined with ruxolitinib were associated with motor recovery to GMFCS level II at 24 months and reversal of interferon pathways in single-cell RNA sequencing, without the effect of each drug being separable; the authors plan staged tapering after 4 years [52]. Corticosteroid withdrawal may be associated with neuroinflammatory flares [52]. Other immunosuppressants studied in CANDLE (ciclosporin, azathioprine, intravenous immunoglobulin) had minimal benefit, and interleukin 1 and tumour necrosis factor blockade fail in interferonopathies [20].

7.5. Anifrolumab

Anifrolumab is a human IgG1κ monoclonal antibody targeting IFNAR1, authorised for adult SLE [78, 81, 82]. In the National Institutes of Health (NIH) experience, 12 patients with SAVI, PRAAS or putative interferonopathies received 300 mg or 5.5 mg/kg intravenously every 4 weeks, alone or with a JAK inhibitor, with varicella-zoster virus prophylaxis; the interferon signature normalised in all and baricitinib dose could be reduced in 10 of 11, but systemic viral infections occurred in 2 (enterovirus; herpesvirus 6 with encephalopathy) [78]. In a series of 4 SAVI patients and 1 CANDLE patient, anifrolumab had an additive effect to baricitinib, sufficed as monotherapy in 2 SAVI patients and allowed corticosteroid tapering [83]. In AGS, the first description is the Boston series, in which 3 patients switched to anifrolumab (5.5 mg/kg monthly) because of limiting adverse effects or inadequate interferon suppression with baricitinib; the drug was well tolerated and allowed baricitinib reduction or discontinuation while maintaining a normal signature [50]. In an adolescent with a de novo IFIH1 variant and steatohepatitis-related cirrhosis, anifrolumab (300 mg intravenously every 4 weeks) normalised liver enzymes and reduced liver elastography from 25.6 to 8.0 kPa at 28 months [79]. Whether the antibody crosses the blood–brain barrier, a central question in AGS, is unknown, and long-term safety in children is not established [78].

The French PNDS mentions the use of anifrolumab in DNASE2 deficiency, SAVI and PRAAS, considers it of interest because its spectrum is more specific to type I interferon than that of JAK inhibitors and accepts it after multidisciplinary discussion in a specialist centre; it also mentions TBK1 and STING inhibitors in development [12].

7.6. Reverse transcriptase inhibitors

The hypothesis that DNA derived from reverse transcription of endogenous retroelements activates cGAS in TREX1, RNASEH2 and SAMHD1 patients provided the rationale for antiretrovirals. In the open-label, single-centre French pilot, 11 patients received abacavir, lamivudine and zidovudine for 12 months at paediatric HIV-1 doses; 8 completed and 3 did not tolerate triple therapy; the 24-ISG interferon score fell from a median of 9.66 to 5.33, with a greater effect in RNase H2 complex patients, and returned to previous values 6 months after discontinuation [84–86]. The open-label, crossover UK phase 2 trial (NCT04731103) [87] included 13 patients aged 1–15 years with RNASEH2B, TREX1, SAMHD1 and RNASEH2C variants; it excluded ADAR and IFIH1, whose signalling does not involve reverse transcription [85]. Abacavir and lamivudine alone did not reduce the interferon score at 6 weeks; the triple combination reduced it at 3 weeks (−2.45; 98.33% CI −4.84 to −0.07), but not at 6 weeks, and IFN-α protein did not fall [85]. Adherence to the triple arm was poor — only 4 of 12 children tolerated 6 weeks because of syrup volume and taste (27 mL twice daily in a 15 kg child) — there were 10 serious adverse events unrelated directly to treatment and one death, and recruitment fell short of the 24-patient target [85]. The authors conclude that evidence is insufficient to establish efficacy or inefficacy [85]. The EULAR/ACR consensus reports reduced interferon scores without demonstrated clinical benefit and makes no recommendation [5]. A CHOP tenofovir and emtricitabine trial was withdrawn in 2025 because, according to the sponsor, other trials had established baricitinib as standard treatment [88]. TPN-101 (censavudine), a LINE-1 reverse transcriptase inhibitor, was studied in a phase 2a trial terminated in February 2025 by a business decision, with 4 patients and no published results [89]; a European registration for the same drug was identified without verification of its status [90].

The French PNDS concludes that reverse transcriptase inhibitors reduced the interferon signature in certain genetic forms of AGS without demonstrated clinical benefit, so they can only be discussed at a multidisciplinary meeting of a specialist centre [12].

7.7. Regulatory status

Sources: [9, 10, 38, 41, 57, 73, 74, 77, 81, 82, 85, 89]. Reimbursement and access in Portugal (INFARMED) and Brazil (ANVISA) for AGS were not investigated; in the jurisdictions consulted there is no approved indication. Lack of reimbursement for JAK1/2 inhibitors in some countries prompted tofacitinib use in a Dutch patient [72]. The Eli Lilly compassionate-use protocol for autoinflammatory syndromes (NCT01724580) allows access on physician request [91].

7.8. Trials and therapeutic studies

Sources: [10, 11, 38, 41, 61, 75–77, 80, 84, 85, 89]. SAE: serious adverse event; RTI: reverse transcriptase inhibitor; ns: non-significant.

None of these studies is randomised or has a concurrent control group except the Italian retrospective comparison, which does not control for severity or disease phase [11]. Results cannot be indirectly compared: populations differ in age, genotype, disease phase and baseline severity, and scales (parental diary, AGS severity scale, GMFM-88) were developed or adapted by the groups themselves [41, 75]. Spontaneous improvement after the encephalopathic phase and spontaneous falls in interferon and CNS inflammation markers confound effect attribution [6, 41, 48]. Mean severity-scale improvements (+0.9 to +1.2 points on an 11-point scale) are small in absolute terms, and motor benefit was confined to the intermediate-severity group [41, 75]. Negative and neutral results — the Japanese study, antiretroviral trial and lack of neuroradiological advantage in the Italian series — should be read alongside positive findings [11, 77, 85]. The congress-presented systematic review is subject to publication bias and does not specify the denominator of evaluable cases [80]. To prepare future trials, the Global Leukodystrophy Initiative Clinical Trial Network defined, through eDelphi consensus and family focus groups, priority outcome domains — motor function, adaptive behaviour and neurological function — with expert disagreement on the likelihood of change over 6–12 months [92].

7.9. Vaccination, infections and COVID-19

There was no consensus on AGS vaccination because anecdotal reports of neurological regression after vaccination were debated; the EULAR/ACR consensus makes no AGS-specific recommendation, recommends avoiding live vaccines on JAK inhibitors or immunosuppressants and considers SARS-CoV-2 mRNA vaccine data insufficient [5]. The baricitinib label recommends updating vaccinations before starting the drug and avoiding live vaccines [9]. The two invasive pneumococcal infections due to serotypes not included in the 13-valent conjugate vaccine in the French study support, according to the authors, vaccination before starting a JAK inhibitor [41]. At the time of the consensus, there was no evidence of a COVID-19 risk differing from the healthy population, and treatment should not be stopped unless contraindicated; in symptomatic infection, adjustment should occur only under expert supervision because of possible flares after discontinuation [5]. Antiviral prophylaxis is not routinely recommended in AGS [5].

The French PNDS (National Diagnosis and Care Protocol), in the absence of published data specific to interferonopathies, applies the 2021 EULAR/PReS recommendations for paediatric rheumatic diseases and the 2014 French recommendations for immunocompromised patients: check vaccination status annually, complete the national schedule and add annual influenza vaccination and pneumococcal and meningococcal vaccines; vaccinations should be updated as early as possible, preferably during a stable phase and before any immunosuppressant, with live vaccines at least 2–4 weeks beforehand, without ever delaying urgent treatment [12]. Two live vaccines are given on the same day or one month apart, and the others require no interval; influenza and pneumococcal vaccines can be given during a flare if not given before; no post-vaccination follow-up is needed, other than advising the family to contact the doctor if signs of disease activity appear, and serious or unexpected adverse effects should be reported to pharmacovigilance [12]. Inactivated or subunit vaccines have no restrictions; with corticosteroid therapy below 20 mg/day or up to 0.5 mg/kg/day prednisone equivalent no loss of immunogenicity has been described, above 20 mg/day the humoral response is lower, and on immunosuppressants (including JAK inhibitors), high-dose corticosteroids (0.5 mg/kg/day or more for 2 weeks) or biologics vaccination against encapsulated bacteria is recommended [12]. Live measles, mumps and rubella and varicella vaccines are contraindicated on JAK inhibitors and may be discussed case by case on low-dose corticosteroids, while BCG and yellow fever vaccines remain contraindicated; after stopping an immunosuppressant, a biologic, immunosuppressive-dose corticosteroids or corticosteroid pulses, the immune response recovers within 3 months to 1 year, and a live vaccine requires an interval of at least 3 months; post-vaccination serology allows boosters to be adjusted, because efficacy may be reduced [12].

Table 7.9a — Vaccination in interferonopathies according to the French PNDS (2024 French schedule) [12]

7.10. Pregnancy, lactation, perioperative care and transition

The sources consulted do not describe pregnancies in women with classical AGS; most patients do not reproduce, but patients with preserved intellect and mild forms reach adulthood [2, 6]. The French PNDS (National Diagnosis and Care Protocol) considers fertility preserved in interferonopathies, recommends a genetics clinic appointment before conception when a pregnancy is planned and, in a pregnant woman, for a possible request for prenatal diagnosis, and asks that pregnancy be planned so that contraindicated drugs can be stopped [12]. JAK inhibitors are potentially teratogenic and are contraindicated in pregnancy and breastfeeding; when a man on a JAK inhibitor fathers a child no measures are needed, because no mutagenesis has been associated; if pregnancy occurs on treatment, the drug (and any associated methotrexate) is stopped, ultrasound surveillance is performed and the case is reported to pharmacovigilance or to the reference centre on teratogenic agents (CRAT), and, in the absence of anomalies, the pregnancy may continue, because normal pregnancies have been described after exposure in the first weeks; resumption after delivery is ideally postponed until the end of breastfeeding, or precludes it [12]. Obstetric surveillance should take into account possible worsening of glaucoma, nephropathy and interstitial lung disease and the presence of antiphospholipid antibodies or a history of thrombosis; in sexually active patients on immunosuppressants, contraception is adapted to antiphospholipid status, with a preference for progestogen-only methods if positive [12]. The PNDS gives washout intervals before conception of 1 week for baricitinib and upadacitinib and 4 weeks for tofacitinib and filgotinib, with no indication for ruxolitinib [12]; the European summaries of product characteristics require effective contraception during and for at least 1 week after baricitinib (Olumiant®) and filgotinib (Jyseleca®), during and for 4 weeks after upadacitinib (Rinvoq®) and tofacitinib (Xeljanz®), and only during treatment with ruxolitinib (Jakavi®), so the PNDS values for upadacitinib and filgotinib are transposed and those of the SmPCs prevail [10, 74, 93–95]. Perioperatively, the neonatal case in section 10 received methylprednisolone for three days around hernia repair while on ruxolitinib [57]; there is no formal recommendation. Sedation for neuroimaging requires risk assessment, and respiratory complications and aspiration are the main practical anaesthetic risk [2, 5]. Transition to adult care is relevant because 68 patients (19.0%) in the 2015 cohort lived beyond 15 years and 8 were over 30 years [6]; the consensus proposes lifelong multidisciplinary follow-up, and the French PNDS proposes a transition model.

According to the PNDS, transition is prepared from 12–14 years, transfer takes place at around 16–18 years and ends with the young adult engagement phase; it requires a written protocol, an identified medical and nursing pair and, preferably, a phase of disease stability, and may rely on a European checklist covering the disease, complications, treatments, sexuality, fertility, pregnancy and risk behaviours [12]. In patients with cognitive impairment, the process follows the model for people with multiple disabilities, because paediatric medico-social support extends to 20 years; the protocol reports episodes of psychiatric decompensation in young adults, attributed to white matter maturation, and adopts the proposals of the 2016 SOFMER recommendation: joint paediatrician–adult physician consultations, an adult primary care physician identified before leaving the paediatric service, a transition programme known to the young person, the family and the institutions, health education, preparation of administrative changes and guardianship before 18 years, and parent groups [12]. Therapeutic patient education, with programmes listed for rare diseases, supports this move to autonomy [12].

7.11. Treatment of allelic diseases and related interferonopathies

In TREX1-related familial chilblain lupus, protection against cold and damp is the first measure; three adults treated with baricitinib 4 mg/day for 3 months had significant improvement of skin lesions and suppression of the interferon signature, with pain remission in one and no serious adverse reactions (off-label) [8, 47]. In RVCL-S, GeneReviews describes retinal laser, bevacizumab for macular oedema, corticosteroids for vasogenic oedema and annual surveillance from the fourth decade, and recommends avoiding intravenous tissue plasminogen activator in ischaemic stroke without large-vessel occlusion; there is no investigational therapy [8, 24]. In SPENCD, prednisolone and azathioprine are the most frequently effective drugs, with partial responses to JAK inhibitors, and myeloma should be screened for if IgG rises [20]. In CANDLE, off-label baricitinib induced sustained clinical remission in 5 of 10 patients in the expanded-access programme; dose reductions above 25% triggered flares, and anti-TNF agents may worsen the disease [20, 96]. The therapeutic approach to SAVI with JAK inhibitors is described in 7.3.

7.12. Developments in the last 12 months

No gene therapy trials, human studies with cGAS or STING inhibitors or specific authorisations for AGS were found in the sources consulted; absence of search results does not demonstrate the absence of developments. Recent reviews identify mechanism-directed therapies as the direction of research [36, 99].

7.13. Guidelines and divergences between sources

Sources: [2, 5, 6, 10, 11, 19, 41, 52, 85, 88]. Decisions adopted in the interpretation column follow the most recent and most specific source, and surveillance intervals are those in section 11.

Table 7.13a — Divergences between the French PNDS on interferonopathies (2024) and other sources

Sources: [5, 6, 9, 10, 12, 38, 39, 74, 93–95].

8. Reproductive Options and Family Counselling

8.1. Inheritance patterns and recurrence risks

Sources: [2, 6]. Carrier identification and prenatal diagnosis require prior identification of the familial variants [2]. For dominant genes, parents of a proband with an apparently de novo variant should be tested, including those appearing unaffected, because penetrance is incomplete [2, 6].

8.2. Heterozygous carriers

Carriers of recessive variants do not develop AGS [2]. Two issues warrant specific counselling. First, heterozygous TREX1 variants are associated with SLE (9 of 417 patients) and chilblain lupus, and C-terminal variants with RVCL-S, raising the unproven possibility of late-onset SLE or RVCL-S risk in heterozygous parents of children with AGS1, depending on the variant [2, 6]. Second, the 2015 cohort found no increase in cancer among carriers, but the role of RNase H2 in removing ribonucleotides from DNA and the case of chronic lymphocytic leukaemia in a SAMHD1 patient justify long-term observation according to the authors [6]. The RNASEH2B p.(Ala177Thr) and ADAR p.(Pro193Ala) variants have a non-negligible carrier frequency in the general population, and the SAMHD1 deletion has a carrier frequency of 1/138 in Ashkenazi Jews, according to a conference abstract cited in the 2015 cohort [6]. In the South African RNU7-1 family, the carrier mother had elevated ISG without disease [16].

8.3. Intrafamilial variability and sibling testing

Severity may differ greatly between siblings with the same genotype, particularly with SAMHD1, RNASEH2B and RNASEH2C: in a series of 26 siblings from 13 families, 5 pairs differed by more than 2 points on the severity scale, and the older sibling was diagnosed at a median of 7.32 years, compared with 1.54 years in the younger [6, 43]. This variability should be explained before prenatal diagnosis, because genotype does not predict severity [2]. Testing asymptomatic siblings enables presymptomatic diagnosis, whose utility is discussed in the context of early treatment; in the French study, a child treated preventively developed neurological disease, and CSF IFN-α was elevated 11 months before symptoms [41, 43].

The French PNDS (National Diagnosis and Care Protocol) considers that disclosure of a hereditary interferonopathy should be accompanied by genetic counselling, with mandatory information on the risks for relatives and on the information to be passed on to them, and on the risk for offspring, together with an offer to study affected relatives; testing of asymptomatic individuals, often minors, should not be offered systematically and is considered only if a specific and early treatment would be possible in the event of a positive result [12]. A geneticist or a genetic counsellor should be offered to the patient, the parents and collateral relatives and when a pregnancy is desired [12].

8.4. Prenatal diagnosis and preimplantation genetic testing

Once familial variants are identified, molecular prenatal diagnosis and PGT are possible [2]. Fetal ultrasound and MRI may show calcifications, and IFN-α was found elevated in fetal blood at 26 weeks in one case, but these findings are not validated tests and their absence does not exclude disease [2]. Counselling should ideally precede pregnancy and be offered to affected young adults, carriers or those at risk; DNA from a proband without a molecular diagnosis should be stored to enable future testing [2]. The EULAR/ACR consensus includes formal genetic counselling in follow-up of all patients [5].

In France, prenatal diagnosis may be offered depending on the interferonopathy, after the opinion of a multidisciplinary prenatal diagnosis centre (CPDPN), and a genetics clinic appointment is recommended before conception or early in pregnancy [12].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and what each figure measures

The true frequency of AGS is unknown [2]. The only population study found is Danish: using national registries and hospital data, it identified 7 patients with genetically confirmed AGS between January 2010 and December 2020 (TREX1 in fewer than 5 and RNASEH2B in 5 or more), with a mean age at diagnosis of 19.4 months [7]. Birth incidence was below 0.76/100 000 live births and mean annual incidence was 0.0539/100 000 person-years (95% CI 0.0217–0.1111) in the population under 18 years [7]. These values measure diagnosed cases in a country with broad access to genetic testing, not prevalence; undiagnosed cases are possible, and the authors suggest applicability only to Nordic countries [7]. The study was funded by the pharmaceutical industry [7].

Orphanet contains two records for AGS: “unknown” worldwide prevalence and European prevalence in the 1–5/10 000 class, sourced from the EMA's 2015 orphan medicinal product designation [1]. This second value is the regulatory ceiling required for orphan designation and not an epidemiological measurement; AGS is several orders of magnitude rarer, so this value should not be used as prevalence [3, 8]. Familial chilblain lupus has a prevalence below 1/1 000,000 (around 10 registered families), RVCL-S prevalence is unknown (fewer than 25 known families), SPENCD has a prevalence below 1/1 000,000 (36 reported cases) and CANDLE/PRAAS around 40 cases or families [8, 20, 24]. The frequency of dyschromatosis symmetrica hereditaria in Japan (1.5/100 000) refers to the skin disease and not ADAR-related AGS [19].

In France, a 2022 extraction from the national rare disease database (BNDMR) counted a few hundred patients with type I interferonopathies as a whole; the figure measures patients registered in reference and competence centres, not prevalence, and does not separate AGS from the other interferonopathies [12].

9.2. Genotype distribution by region

Proportions by gene derive from predominantly European and North American referral cohorts and vary by population [3]. In the 2015 international cohort (299 families), RNASEH2B accounted for 36% of families, TREX1 22%, SAMHD1 13%, RNASEH2C 12%, ADAR 6% and RNASEH2A 5%, with 9 IFIH1 families [6]. In the CHOP cohort (USA, 167 patients) the distribution was RNASEH2B 29.9%, ADAR 20.4%, TREX1 15.6%, SAMHD1 15.0%, IFIH1 11.4%, RNASEH2A 4.2%, RNASEH2C 1.8% and RNU7-1 1.8% [15]. The Italian cohort has more RNASEH2B and less TREX1 than international series [51]. The German biomarker cohort included 55 patients, and the Danish cohort only TREX1 and RNASEH2B [7, 62].

9.3. Founder variants and specific populations

AGS has been described in all ethnic backgrounds [2]. Consanguinity increases the probability of recessive forms and dual diagnoses, as in the Turkish case in section 10 [57]. The 2015 cohort included collaborators from Lisbon (Hospital Dona Estefânia) and Ribeirão Preto (Universidade de São Paulo), and the discovery study of LSM11 and RNU7-1 had co-authors from Ribeirão Preto, Goiânia and Cape Town; the sources do not disaggregate patients by country, and no epidemiological data from Portugal or Brazil were found for AGS [6, 18]. In the differential diagnosis, the PSMB8 p.(Thr75Met) variant is recurrent in Portuguese patients with CANDLE/JMP [20]. Absence of data in the sources consulted does not demonstrate that they do not exist.

9.4. Special populations

Patients with late onset, spastic paraparesis and preserved intellect may be diagnosed only in adolescence or adulthood, and AGS should be considered in the differential diagnosis of hereditary spastic paraparesis [6, 45]. Adults with allelic TREX1 diseases (chilblain lupus, RVCL-S) and ADAR diseases (psoriasis) are followed by adult dermatology, rheumatology, ophthalmology and neurology [8, 24, 25]. Patients with RNASEH2B, the most frequent genotype, are more likely to have a negative ISG signature, which may delay diagnosis if the test is used as a filter [39, 63].

9.5. Reference networks and patient associations

In Europe, ERN RITA (European Reference Network on Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases) brings together 71 centres in 25 countries, with a dedicated autoinflammatory disease stream and its own registry [13]. ERN-RND (European Reference Network on Rare Neurological Diseases) has a leukodystrophy group with standards of care in several languages; AGS is not named on the page consulted, and its inclusion within this network corresponds to its classification as a genetic leukoencephalopathy [14, 58]. The Italian AGS network includes an ERN RITA centre [11]. Patient associations include the International Aicardi-Goutières Syndrome Association (IAGSA, Italy), with a scientific committee; the AGS Advocacy Association (USA), dedicated to research funding and family support; and the United Leukodystrophy Foundation (USA) [2, 100–102]. The CHOP Myelin Disorders Biorepository Project maintains a natural history cohort, and Institut Imagine coordinates the European interferonopathy cohort [15, 97].

In France, the RAISE reference centre (paediatric rheumatology, with sites in Paris, Lyon and Lille, among others) coordinates the PNDS with the FAI²R (rare autoimmune and autoinflammatory diseases) and BRAIN-TEAM (rare diseases of the central nervous system) networks, joined by DEFISCIENCE (neurodevelopment), MaRIH (immuno-haematology) and RespiFIL (rare respiratory diseases); interferon signature testing is performed routinely at the reference laboratory of Hôpital Lyon Sud, therapeutic patient education programmes are listed in a national directory and, among patient associations, ELA (Association européenne contre les leucodystrophies) supports the neurological forms [12].

10. Illustrative Clinical Case

Konak and colleagues described in 2026 a Turkish newborn, born to consanguineous parents and a 29-year-old mother, delivered by caesarean section at 38 weeks and 5 days, weighing 2650 g (10–50th percentiles), with a head circumference of 31.5 cm and length of 42 cm, both below the 3rd percentile [57]. He was admitted to the neonatal intensive care unit on day 16 of life with cholestatic jaundice, a generalised ecchymotic and purpuric “blueberry muffin” rash, leukocoria, microcephaly, massive hepatosplenomegaly and bilateral inguinal hernias with hydrocele [57].

Laboratory tests showed bicytopenia (leukocytes 1.50 × 10³/µL and platelets 28 × 10³/µL on day 16), cholestasis (total bilirubin 19.11 mg/dL, direct bilirubin 15.49 mg/dL), elevated transaminases and ESR, peak ferritin of 7175 ng/mL on day 18 and hypertriglyceridaemia up to 345 mg/dL [57]. The patient met 5 of the 8 HLH-2004 criteria, but marrow was hypocellular without haemophagocytosis, and soluble CD25 and NK cell cytotoxicity were unavailable; the authors interpreted the presentation as AGS-associated macrophage activation syndrome-like hyperinflammation, rather than primary HLH [57]. TORCH testing was negative, cytomegalovirus PCR was negative in blood, urine and CSF, metabolic testing revealed no alternative diagnosis, and immunoglobulins, lymphocyte subsets, complement and autoantibodies were normal [57]. CT and MRI showed diffuse periventricular and subcortical calcifications with diffusion restriction, bilateral intraventricular haemorrhage, cerebral atrophy and white matter volume loss; on MRI (Figure 1 of the article), SWI sequences show hypointensity in the basal ganglia and deep and periventricular white matter, compatible with calcification, and T1 sequences show symmetrical hyperintensities at the same sites (Figure 1) [57].

Ophthalmological examination under anaesthesia, at around one month, showed bilateral corneal oedema, corneal diameters of 11.5–12 mm and intraocular pressure of 30–35 mmHg, compatible with severe congenital glaucoma; after trabeculotomy, pressure fell to 13–14 mmHg (Figure 2) [57]. Exome sequencing, with CNV and mitochondrial DNA analysis, identified homozygosity for RNASEH2B NM_024570.4:c.554T>G p.(Val185Gly), classified as pathogenic or likely pathogenic in ClinVar, confirming AGS2, and for CYP1B1 NM_000104.4:c.1310C>T p.(Pro437Leu), pathogenic according to the ClinGen glaucoma curation panel, a cause of primary congenital glaucoma; consanguinity explained this dual diagnosis, and parental segregation was not performed [57].

At the referring hospital, the newborn received intravenous dexamethasone (2 mg/kg/day) and intravenous immunoglobulin (1 g/kg twice weekly) between days 13 and 16 for suspected viral HLH, discontinued without tapering on transfer, and ganciclovir until cytomegalovirus was excluded [57]. Without access to an interferon signature, the team initiated empirical ruxolitinib at 0.2 mg/kg/day on day 34, before molecular confirmation and off-label, and increased it to 0.4 mg/kg/day on day 65; herniorrhaphy was performed on day 53, with methylprednisolone 2 mg/kg/day on days 55 to 57 [57]. Ferritin fell from 2740 ng/mL (day 34) to 737 ng/mL (day 135) (Figure 3), platelets recovered to 136 × 10³/µL on day 93, total bilirubin normalised (0.50 mg/dL) and skin lesions and hepatosplenomegaly regressed, without adverse effects identified in the first month of treatment [57]. The authors do not attribute the initial improvement, before day 34, to the JAK inhibitor, and consider the course compatible with disease modification, but not proof of it [57].

The case illustrates neonatal presentation resembling congenital infection — more frequent with TREX1, but possible with RNASEH2B —, neonatal hyperinflammation as a rare presentation, reviewed by the authors in four previous reports, and glaucoma as a manifestation that here had a second genetic cause [6, 57]. The decision to start a JAK inhibitor in the neonatal period without genetic confirmation does not correspond to practice recommended by the consensus, which requires genetic diagnosis; lack of an available interferon signature motivated the authors' decision [5, 57].

11. Prognosis and Long-Term Follow-Up

11.1. Natural history prognosis

Most patients are left with severe intellectual and motor disability, with variability between siblings [2]. In the 2015 cohort, 210 of 285 patients (74%) had no useful gross motor, manual or communication function (level V on GMFCS, MACS and CFCS scales), and only 14 of 294 walked without support or with minimal support [6]. Function was better with RNASEH2B, SAMHD1, ADAR and IFIH1: among patients with a level below V, 32 had RNASEH2B, 19 SAMHD1, 10 ADAR and 6 IFIH1, compared with 3 TREX1, 2 RNASEH2A and 3 RNASEH2C [6]. In the MDBP cohort, the AGS severity scale had a median of 4 (interquartile range 7), with TREX1 as the most severe genotype (median 2), and microcephaly, the need for tube feeding and seizures were associated with a worse score [15]. CSF interferon activity in the first year after onset correlated with disability [6]. ADAR patients with bilateral striatal necrosis and patients with pure spastic paraparesis may retain intellect, but in a group of 33 biallelic ADAR1 patients 79% had severe disability or had died [6, 52].

Mortality correlates with genotype. In the 2007 cohort, 34.3% of patients with TREX1, RNASEH2A or RNASEH2C — a pooled value for the three genes — had died, compared with 8.0% with RNASEH2B (p=0.001) [2, 42]. In the 2015 cohort, 69 of 357 patients (19.3%) had died, 37 of them in the first 5 years; TREX1 had the highest number of deaths (26; 33.3% of TREX1 patients) [6]. Conversely, 68 patients (19.0%) lived beyond 15 years and 8 were alive over 30 years [6]. These percentages describe the proportion of known deaths at data collection in non-prospective cohorts with incomplete follow-up, rather than a lifetime risk of death; the authors did not derive formal rates [6]. Respiratory complications are a major cause of death [3]. RNU7-1 patients have higher mortality and greater organ involvement [17].

11.2. Prognosis with treatment

Available data do not allow estimation of the effect of JAK inhibitors on long-term survival or disability. Open-label studies show small improvements on the severity scale (around 1 point out of 11) and milestone gains in some patients, with greater benefit in intermediate or mild phenotypes and with treatment during the inflammatory phase [11, 38, 41, 75]. Established neurological damage does not regress [5, 8]. The review of 97 published patients receiving JAK inhibitors recorded death in 7.4% of evaluable patients, a value subject to publication bias [80].

11.3. Surveillance

The table follows Table 4 of the EULAR/ACR consensus and recommendations from the 2015 cohort; without active disease, the consensus proposes visits every 3 months to assess activity and toxicity [5, 6].

The 2015 cohort recommends proactive screening for glaucoma, hypothyroidism, cardiomyopathy and neuropathy, with lifelong, perhaps annual, surveillance of glaucoma and thyroid function [6]. GeneReviews adds neonatal surveillance for signs of diabetes insipidus and spinal surveillance, without defined intervals [2]. In carriers and relatives, no formal surveillance is established; in parents heterozygous for C-terminal TREX1 variants, RVCL-S surveillance described in GeneReviews (annually from the fourth decade) applies only if the disease is diagnosed [2, 24]. Plasma biomarkers of neurological injury (NfL, GFAP) and CSF neopterin are being evaluated for response monitoring [61, 62].

The French PNDS (National Diagnosis and Care Protocol) lists the complications requiring specialist care during follow-up: chronic respiratory failure with oxygen therapy and lung transplantation (SAVI, COPA syndrome); epilepsy, pain and dystonia or spasticity, with prevention of status epilepticus and status dystonicus; glaucoma with medical or surgical treatment; joint deformities, dislocations, scoliosis, periarticular calcifications and tendon ruptures; small-vessel vasculitis with tissue loss and moyamoya; dental complications; lupus-like glomerulonephritis, IgA nephropathy and, exceptionally, AA amyloidosis, to be considered in the presence of proteinuria or impaired renal function; cardiomyopathy, pulmonary hypertension, pericarditis and valvular and aortic calcifications; and physical protection against chilblains each winter [12].

12. Summary and Final Considerations

Aicardi–Goutières syndrome is a monogenic inflammatory encephalopathy in which self nucleic acids, inadequately degraded, edited or packaged, activate antiviral sensors and sustain chronic type I interferon production [18, 34]. Nine genes are established: TREX1, the three RNase H2 genes, SAMHD1, ADAR, IFIH1, LSM11 and RNU7-1; inheritance is recessive in most, with specific dominant variants in TREX1 and ADAR and dominant gain of function in IFIH1 [2, 5]. Subtype numbering should follow OMIM and always be accompanied by the gene, because at least one reference book uses a different order [3, 34].

Clinically, disease manifests mainly in the first year of life, through an encephalopathic phase lasting months with irritability, fever without a focus, loss of skills and acquired microcephaly, followed by stabilisation with usually severe deficits [2, 6]. Around a quarter of patients have prenatal onset, sometimes with a presentation indistinguishable from congenital infection, and a minority have late or atypical forms — spastic paraparesis, bilateral striatal necrosis, isolated chilblains — extending the differential diagnosis to cerebral palsy and hereditary paraparesis [6, 46]. Chilblains, glaucoma, SAMHD1 arteriopathy, endocrinopathies, cardiomyopathy and pulmonary hypertension define systemic surveillance [5, 6].

Diagnosis requires genetic confirmation by NGS with CNV analysis, attention to splicing and synonymous variants and coverage of RNU7-1; CT complements MRI for calcification, and the ISG signature, lymphocytosis and CSF IFN-α support diagnosis but decline with age and are less sensitive in RNASEH2B patients [5, 17, 39, 63]. Disease frequency is unknown; the only population datum, from Denmark, suggests an incidence below 1/130 000 live births, and the European Orphanet value is a regulatory ceiling [1, 7].

No drug has an approved indication; the 2024 French PNDS (National Diagnosis and Care Protocol) reserves JAK inhibitors for a multidisciplinary decision in a specialist centre and considers their neurological benefit in AGS uncertain [12]. JAK inhibitors, used off-label in specialist centres and recommended as beneficial by the EULAR/ACR consensus, consistently improve cutaneous and systemic manifestations and discomfort, but their neurological effect is small and heterogeneous, greater when started early and in less severe phenotypes, and accompanied by infectious and haematological risks requiring structured monitoring [5, 11, 38, 41]. Reverse transcriptase inhibitors have not demonstrated clinical benefit, and anifrolumab is an investigational alternative [50, 85]. Genetic counselling should incorporate intrafamilial variability, incomplete penetrance of dominant variants and the uncertain risk of allelic TREX1 diseases in carriers [2, 6]. The absence of controlled trials, spontaneous improvement after the encephalopathic phase and lack of validated CNS injury biomarkers are the main gaps, and ongoing natural history cohorts and definition of patient-centred outcomes are the steps needed to address them [62, 92, 97].

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