Aicardi-Goutières Syndrome

Clinical characteristics.

Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.

Diagnosis/testing.

The diagnosis of AGS is established in a proband with typical clinical findings and characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes); AND/OR by identification of one of the following:

• Biallelic pathogenic variants in ADAR, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, or TREX1
• Specific heterozygous autosomal dominant pathogenic variants in TREX1 and ADAR
• A variety of heterozygous autosomal dominant pathogenic variants in IFIH1

Management.

Treatment of manifestations: Chest physiotherapy and treatment of respiratory complications; attention to diet and feeding methods to assure adequate caloric intake and avoid aspiration; management of seizures using standard protocols.

Surveillance: Monitoring for signs of diabetes insipidus in the neonatal period; repeat ophthalmologic examinations at least for the first few years of life to evaluate for evidence of glaucoma; monitoring for evidence of scoliosis, insulin-dependent diabetes mellitus, and hypothyroidism.

Genetic counseling.

AGS is most frequently inherited in an autosomal recessive manner; in a few instances the disease can result from specific de novo or inherited autosomal dominant pathogenic variants in ADAR or TREX1, and a variety of heterozygous autosomal dominant pathogenic variants in IFIH1. At conception, each sib of an affected individual with autosomal recessive AGS has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Individuals with AGS do not typically reproduce. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk for AGS, and preimplantation genetic testing are possible options.

Suggestive Findings

Aicardi-Goutières syndrome (AGS) should be suspected in individuals with the following clinical, neuroimaging, and supportive laboratory findings [Goutières et al 1998, Lanzi et al 2002, Rice et al 2007b, Livingston et al 2013].

Clinical features

• Encephalopathy and/or significant intellectual disability
• Acquired microcephaly during the first year of life
• Dystonia and spasticity
• Sterile pyrexias
• Hepatosplenomegaly
• Chilblain lesions on the feet, hands, ears, and sometimes more generalized mottling of the skin. See Figure 1.

Figure 1.

Examples of chilblains seen in AGS Rice et al [2007b]; reprinted with permission of The American Journal of Human Genetics, University of Chicago Press.

Exclusion criteria include the following:

• Evidence of prenatal/perinatal infection including, but not limited to, CMV, toxoplasmosis, rubella, herpes simplex, Zika, and HIV
• Evidence of a known other metabolic disorder or neurodegenerative disorder

Neuroimaging

• Calcification (best visualized on CT scan) of the basal ganglia, particularly the putamen, globus pallidus and thalamus but also extending into the white matter, sometimes in a para- (rather than true peri-) ventricular distribution [Lanzi et al 2002, Uggetti et al 2009, Livingston et al 2013]. See Figure 2.
  Note: Intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units.
• White matter changes, particularly affecting the frontotemporal regions with (in severe cases) temporal lobe cyst-like formation. See Figure 3.
  On MRI, appears on T₂-weighted images as a hyperintense signal most commonly located around the horns of the ventricles (Figure 3B)
• Cerebral atrophy, which may be progressive and involve the periventricular white matter and sulci
  Cerebellar atrophy and brain stem atrophy may also be prominent (Figure 3D) [Crow et al 2004a, Sanchis et al 2005].
• Bilateral striatal necrosis
• Intracerebral vasculopathy including intracranial stenosis, moyamoya, and aneurysms

Figure 2.

Examples of intracranial calcification on CT scan in individuals with AGS. Calcification is seen: A. In the basal ganglia;

Figure 3.

The spectrum of brain changes seen on MRI in AGS A. Hypointensity on T₁-weighted imaging of the white matter

Establishing the Diagnosis

The diagnosis of AGS is established in a proband with typical clinical findings and characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes) and/or by the identification of biallelic pathogenic variants in ADAR, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, or TREX1; specific heterozygous autosomal dominant pathogenic variants in TREX1 and ADAR; or a variety of heterozygous autosomal dominant pathogenic variants in IFIH1.

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing can be pursued based on the individual's ethnicity and/or in the order in which pathogenic variants most commonly occur (see Table 1).

• If only one pathogenic variant is identified in RNASEH2A, RNASEH2B, RNASEH2C, or SAMHD1, gene-targeted deletion/duplication analysis can be considered next.
• Gene-targeted deletion/duplication analysis may also be considered if a heterozygous pathogenic variant that is not known to be associated with autosomal dominant AGS is identified in TREX1 or ADAR.

A multigene panel that includes ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, TREX1, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and TREX1) fails to confirm a diagnosis in an individual with features of AGS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

In its most characteristic form, Aicardi-Goutières syndrome (AGS) can be considered an early-onset encephalopathy associated with significant intellectual and physical disability.

Pregnancy, delivery, and the neonatal period are normal in approximately 80% of infants with Aicardi-Goutières syndrome (AGS) [Rice et al 2007b]. However, brain calcifications can be identified in utero [Le Garrec et al 2005] and 20% of cases, mainly those caused by biallelic pathogenic variants in TREX1, present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture reminiscent of congenital infection.

All other affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. The majority of these later-presenting infants exhibit subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. The encephalopathic phase usually lasts several months. The opinion of most pediatricians caring for such children is that the disease does not progress beyond the encephalopathic period; occasionally, however, affected individuals do appear to show progression and/or episodes of regression. Death is usually considered to be secondary to the neurologic damage incurred during the initial disease episode, not to further regression. Several affected individuals older than age 30 years show no obvious signs of disease progression.

Neurologic features. Typically, affected individuals have peripheral spasticity, dystonic posturing (particularly of the upper limbs), truncal hypotonia, and poor head control. Seizures are reported in up to half of affected children, but are usually relatively easily controlled [Goutières et al 1998, Rice et al 2007b]. A number of children demonstrate a marked startle reaction to sudden noise, and the differentiation from epilepsy can be difficult. Most affected individuals have severe intellectual and physical impairment. Variability in the severity of the neurologic outcome can be observed among sibs. Most affected children exhibit a severe acquired microcephaly; in children with preserved intellect head circumference can be normal.

Hearing is almost always normal.

Ophthalmology. Visual function varies from normal to cortical blindness. Ocular structures are almost invariably normal on examination. However, there is a risk of congenital glaucoma or later-onset glaucoma [Crow et al 2004a, Crow et al 2015].

Skin lesions. As many as 40% of affected individuals [Rice et al 2007b] have skin lesions with chilblains on the fingers and toes and sometimes the ears and other pressure points (e.g., elbows) [Tolmie et al 1995, Stephenson 2002] (see Figure 1). The cutaneous lesions may be complicated by periungual infection and necrosis.

Other

• Intracranial large-vessel disease. An additional previously undescribed feature of AGS, which so far appears to be almost exclusively related to biallelic pathogenic variants in SAMHD1, is intracranial large-vessel disease causing both intracranial stenoses (in some cases reminiscent of moyamoya syndrome) and aneurysms (see Phenotype Correlations by Gene) [Ramesh et al 2010, Thiele et al 2010, du Moulin et al 2011, Xin et al 2011].
• Refractory four-limb dystonia. Several individuals with ADAR pathogenic variants have been reported to demonstrate an acute or subacute onset of refractory four-limb dystonia starting between age eight months and five years [Livingston et al 2014a, Crow et al 2015] (see Phenotype Correlations by Gene).
  • Individuals can be developmentally normal at initial presentation.
  • This phenotype can occur due to either biallelic pathogenic variants in ADAR or the autosomal dominant pathogenic variant p.Gly1007Arg in ADAR.
  • Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in ADAR or the recurrent dominant pathogenic p.Gly1007Arg variant in ADAR are typically associated with an upregulation of ISGs.

Additional infrequently observed features of AGS are summarized in Table 2.

Neuroimaging/neuropathologic findings

• Calcifications on neuroimaging:
  • Are often punctate but may be dense and rock-like;
  • When identified at diagnosis tend to remain stable, although progression can be observed [Lanzi et al 2002, Lanzi et al 2005];
  • Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [Aicardi & Goutières 1984].
• The main neuropathologic findings identified in severely affected individuals include [Kumar et al 1998, Barth 2002]:
  • Diffuse but nonhomogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown;
  • Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy;
  • Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei;
  • Calcification in the media, adventitia, and perivascular spaces of small vessels;
  • Inflammation in the leptomeninges and areas of necrosis.

Phenotype Correlations by Gene

In general, the early-onset neonatal form of AGS is most frequently seen in association with biallelic pathogenic variants in RNASEH2A, RNASEH2C, or TREX1. The later-onset presentation (sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurologic function) is most frequently seen in association with biallelic pathogenic variants in RNASEH2B, SAMHD1, or ADAR but may also be seen in individuals who have an autosomal dominant heterozygous pathogenic variant in ADAR or IFIH1 [Crow et al 2015].

Mortality is correlated with genotype: 34% of individuals with RNASEH2A, RNASEH2C, and TREX1 pathogenic variants were known to have died compared to 8% with RNASEH2B pathogenic variants (p=0.001) [Rice et al 2007b]. The mortality associated with other genotypes is less clear.

ADAR. Pathogenic variants in ADAR have been associated with a clinical presentation of acute bilateral striatal necrosis.

A subgroup of individuals with ADAR pathogenic variants can present with symmetric signal changes in the caudate and putamen, often associated with swelling and later shrinkage in the context of an acute or subacute onset of refractory four-limb dystonia. Cases have been identified with onset as late as age four years on a background of completely normal development [La Piana et al 2014, Livingston et al 2014a].

ADAR-related disease should be considered in the differential diagnosis of apparently nonsyndromic bilateral striatal necrosis (BSN) with severe dystonia of varying evolution. The finding of an interferon signature provides a useful screening test for the presence of ADAR pathogenic variants in this context.

RNASEH2B. Some individuals with biallelic pathogenic variants in RNASEH2B have relatively preserved intellectual function, with a few having a completely normal IQ and head circumference [McEntagart et al 1998].

RNASEH2C. A family with a recurrent Asian founder variant in RNASEH2C and striking intrafamilial variability has been described [Crow et al 2015].

SAMHD1

• Intracerebral vasculopathy, including intracranial stenosis and aneurysms, is observed more frequently in individuals who have biallelic pathogenic variants in SAMHD1.
• Dale et al [2010] reported two sibs who had biallelic null variants in SAMHD1. The older girl showed mild intellectual disability with microcephaly. Her younger brother had significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains and recurrent mouth ulcers. One of the sibs had a chronic progressive deforming arthropathy of the small and large joints with secondary contractures. Similar joint involvement was described by Ramantani et al [2010] (see also Crow et al [2015]).
• Biallelic pathogenic variants in SAMHD1 are most frequently associated with chilblains and glaucoma [Crow et al 2015].

Nomenclature

The microcephaly-intracranial calcification syndrome (MICS; also known as pseudo-TORCH syndrome or Baraitser-Reardon syndrome) was previously differentiated from AGS on the basis of congenital microcephaly and the presence of non-neurologic abnormalities including elevation of liver enzymes, hepatomegaly, and thrombocytopenia at birth [Reardon et al 1994]. However, recent studies have shown that these same features can be seen in persons with AGS in whom pathogenic variants in one of the associated genes have been identified [Rice et al 2007b]. Of note, in the majority of MICS cases reported no information is available on CSF cell count and IFN-α concentration; thus it is probable that most cases of MICS are in fact AGS.

"Familial systemic lupus erythematosus." Dale et al [2000] described two children of consanguineous parents with early-onset encephalopathy, intracranial calcifications, chilblain skin lesions, and the progressive production of high levels of autoantibodies. CSF was not analyzed. These cases most likely represent AGS [Aicardi & Goutières 2000]. Additional individuals with AGS who have signs and symptoms similar to systemic lupus erythematosus have also been described.

Prevalence

The actual frequency of AGS is unknown.

Pathogenic variants have been found in affected individuals of all ethnic origins [Crow et al 2006a, Crow et al 2006b, Rice et al 2007b, Rice et al 2013b] (see Table 1).