We report three siblings, two of whom had a neuropathological study, with a new subtype of congenital ponto-cerebellar atrophy (PCH). In addition to the brain stem and cerebellar anomalies common to all types of this heterogeneous condition, there were unique developmental defects in the telencephalon: absence of the claustrum, diffuse cortical changes particularly in the insula and an extremely small brain. In an attempt to shed some light on the pathogenesis of this developmental disorder, we have analyzed the pattern of brain stem and cerebellar abnormalities in ours and in previously reported patients with PCH, to possibly distinguish primary from secondary effects of the mutant gene upon the cerebellar circuitry, and compared our patients' cerebellar and cerebral defects to those of some other human brain malformations and to mutant mice with both hindbrain and forebrain anomalies. Although this and previous observations of familial congenital PCH with apparent autosomal recessive inheritance spawn the endeavor to compare and classify patients into subgroups, any final classification must await identification and molecular characterization of the causal gene(s).