We present two siblings with congenital and progressive encephalopathy associated with systemic lupus erythematosus. The two brothers presented soon after birth with an encephalopathy associated with intracranial calcification (=2), intrauterine growth retardation (= 2), hepatitis (= 1) and thrombocytopenia (= 1), mimicking a congenital virus infection. Within the first year of life both children developed hypocomplementaemia and systemic lupus erythematosus (SLE), the main features of which were a discoid lupus-like rash on the hands and feet and the progressive production of high levels of autoantibodies. Both children were severely handicapped and died in early childhood from streptococcal infections. There are many causes of congenital encephalopathy with intracranial calcification. The early development of systemic lupus in these children suggested that their cerebral disease formed part of an autoimmune process. Complement levels and autoantibody profiles should be considered part of the investigation of a child with congenital infection-like syndrome, particularly when there are progressive dermatological complications.

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Objective. Blau syndrome is characterized by noncaseating granulomatous arthritis, dermatitis, and uveitis, and results from gain-of-function NOD2 mutations. This study was undertaken to identify the genetic cause of the disease in a family with 3 members with Blau syndrome.Methods. We studied a family with 3 affected members across 2 consecutive generations. The children's symptoms started early (at 6 and 7 months of age) and included polyarthritis, dermatitis, uveitis, and fever. In contrast, the father's symptoms started later (at 22 years of age) and included noncaseating granulomatous dermatitis and uveitis. We analyzed the NOD2 gene in all patients by both the Sanger method of DNA sequencing and amplicon-based deep sequencing using an Ion Torrent PGM platform.Results. Sanger chromatograms revealed the heterozygous c.1001G>A transition in both children, which resulted in the p.Arg334Gln mutation that causes Blau syndrome. In contrast, the father's chromatograms revealed a small peak of adenine at the c.1001 position, suggesting the presence of a somatic NOD2 mutation. To evaluate this hypothesis, we performed ampliconbased deep sequencing using DNA from different tissues, which confirmed a variable degree (0.9-12.9%) of somatic NOD2 mosaicism. The previous detection of the NOD2 mutation in his daughters strongly suggests the presence of gonosomal (somatic plus gonadal) NOD2 mosaicism in the father. Comparative analyses with Blau syndrome patients carrying the germline p.Arg334Gln NOD2 mutation revealed late onset of the disease, a mild inflammatory phenotype, and an absence of complications in patients with NOD2 mosaicism.Conclusion. This is the first description of gonosomal NOD2 mosaicism as the cause of intrafamilial recurrence of Blau syndrome. Our findings also indicate that Blau syndrome includes more diverse and milder phenotypes than previously described.