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Just over 120 cases have been reported in the literature so far.

The majority of affected infants are born at full term with normal growth parameters. Onset occurs within the first few days or month of life with severe, subacute encephalopathy (feeding problems, irritability and psychomotor regression or delay) associated with epilepsy (53% of cases), chilblain skin lesions on the extremities (43% of cases) and episodes of aseptic febrile illness (40% of cases). Symptoms progress over several months (with the development of microcephaly and pyramidal signs) before the disease course stabilises. However, less severe forms have been described with onset after 1 year of age and preservation of language skills and cognitive function, and normal head circumference. The phenotype shows inter- and intrafamilial variation.

In 2006, causative mutations were identified in four genes: TREX1, encoding a 3'->5' exonuclease, and in RNASEH2A, RNASEH2B and RNASEH2C, genes encoding subunits of the RNase H2 endonuclease complex. TREX1 (25% of cases), RNASEH2C (14% of cases) and RNASEH2A (4% of cases) mutations result in a severe phenotype, whereas RNASEH2B (41% of cases) mutations generally lead to a milder phenotype. No mutations in any of these genes are found in the remaining cases.

Calcification (involving the basal ganglia and white matter), cystic leukodystrophy (predominantly frontotemporal) and cortical-subcortical atrophy are the cardinal features for diagnosis, often associated with atrophy of the corpus callosum, brain stem and cerebellum. Elevated IFN-alpha levels and CSF lymphocytosis are very frequent but not constant findings (90% and 75% of cases, respectively) in the initial stage of the disease but tend to normalise or resolve within a few years. The diagnosis is confirmed by detection of a mutation in one of the four disease-causing genes.

The principle differential diagnoses are TORCH congenital infections (toxoplasma, rubella, CMV, HSV1 and HSV2).

Prenatal diagnosis is feasible through molecular analysis of amniotic fluid or trophoblasts.

Transmission is autosomal recessive but rare cases of autosomal dominant inheritance have been reported.

Treatment is symptomatic (management of the feeding problems, psychomotor delay and, if present, epilepsy).

Around 80% of patients presenting with the severe form die within the first 10 years of life but prolonged survival after the first decade of life has been reported in milder forms.