The clinical features, the underlying CIAS1 mutation, and the results of
cytokine analyses are described for a 10-year-old German boy with
neonatal-onset multisystem inflammatory disease, whose condition improved with age. Disease onset occurred at 26 months of age with predominantly cutaneous (urticarial
rash) and neurologic (
headache, chronic meningitis) symptoms including early bilateral optic nerve
atrophy, whereas articular manifestations were mild. Sequence analysis of exon 3 of the CIAS1 gene revealed heterozygosity for a novel missense mutation. A T515C transition led to the replacement of
isoleucine by
threonine at
amino acid position 172 (I172T) in a region of cryopyrin flanking the
PYRIN and NACHT domains. This mutation was not present in the parents or in 11 controls and therefore was considered to be a de novo mutation.
Enzyme-linked
immunosorbent assays were performed to determine
interleukin-6 and soluble
tumor necrosis factor receptor superfamily 1B levels in the patient's serum and cerebrospinal fluid (CSF). Concentrations were highly elevated in the CSF, whereas corresponding serum levels remained low. The strong
cytokine activation in the CSF corresponded with the
neurologic symptoms. Local activation of intrathecal macrophages may therefore be an important pathogenetic mechanism. CSF
cytokine levels decreased to normal under
corticosteroid and intrathecal
methotrexate therapy. When the boy reached the age of 5.5 years, treatment was stopped, and he has remained relapse-free.