Genetics of childhood disorders: XXXIII. Autoimmunity, part 6: poststreptococcal autoimmunity.

1479 In the late 1980s, studies of children with Sydenham chorea (SC), the neurological manifestation of rheumatic fever, suggested that the disorder might serve as a useful model of pathophysiology for some forms of childhood-onset obsessivecompulsive disorder (OCD) and tic disorders. The disorders share anatomic similarities. Both OCD and SC have evidence of basal ganglia dysfunction, particularly in the caudate nucleus, which is thought to disrupt signals traveling along the orbitofrontal-striatal pathways. Furthermore, over 70% of children with SC reported that they had experienced an abrupt onset of repetitive, unwanted thoughts and behaviors 2 to 4 weeks before the onset of their chorea. These obsessions and compulsions peaked in intensity concomitantly with the chorea and waned away slowly over the ensuing months. Because the obsessive-compulsive symptoms began earlier than the chorea, it seemed possible that poststreptococcal OCD might occur in the absence of chorea, a hypothesis confirmed by prospective observations of a large cohort of children with primary OCD. Among those children, a subgroup was noted to have dramatic symptom exacerbations following infections with group A β-hemolytic streptococcal bacteria (GABHS) such as occurs with strep throat and scarlet fever. The symptom exacerbations were accompanied by a cluster of comorbid symptoms, including emotional lability, separation anxiety, and attentional difficulties. The children were young (6–7 years old at symptom onset), predominantly male, and had frequent comorbid tics. To indicate the subgroup’s common clinical characteristics and presumed pathophysiology, it was identified by the acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections). The etiology proposed for the PANDAS subgroup is similar to that postulated for SC. In SC, host susceptibility is thought to play a crucial role in symptom expression, as fewer than 5% of children are vulnerable to poststreptococcal sequelae. Familial clustering suggests that genetic factors are involved in the susceptibility, but is not the sole explanation as developmental and immunological factors may also play a part. The constitution of the streptococcal bacteria appears to play an etiological role in rheumatic fever and other poststreptococcal sequelae. Although most strains of GABHS produce only acute symptoms, certain “rheumatogenic” strains incite the production of antibodies that cross-react with host tissues, producing an “autoimmune”; reaction. Unlike typical autoimmune disorders, the autoantibodies in rheumatic fever are not Genetics of Childhood Disorders: XXXIII. Autoimmunity, Part 6: Poststreptococcal Autoimmunity