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.
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