Typical Pallister-Hall syndrome consists of hypothalamic hamartoma with or without pituitary dysplasia or dysfunction, polydactyly, imperforate anus, and other anomalies of the respiratory, renal and cardiac systems. It was originally described in 6 sporadic cases, all of whom died in the neonatal period. Subsequently, we and others have evaluated several cases of families affected with a milder variation of this disorder, which is inherited in an autosomal dominant pattern. The three families (families A, B & C) summarized in this report include families with 4, 12, and 22 affected members, respectively. All of the affecteds in the pedigrees have polydactyly, which is variable in the number of limbs affected (2-4) and in the type of polydactyly (postaxial or central). MRI scans of the brain have been performed on 14 patients and 12 of those showed hypothalamic hamartoma +/- pituitary dysplasia. One subject had an autopsy performed for forensic reasons and this examination revealed a hypothalamic hamartoma. Pituitary dysfunction is not seen in these mildly affected families. Among these three families, there are 1, 4, and 10 obligate heterozygotes, respectively. Among these 15 obligate heterozygotes, all 15 show some signs of the disorder and all of them have polydactyly. All but one of the obligate heterozygotes have a hypothalamic hamartoma on MRI examination. In addition to these clinical studies, we have performed a genetic analysis to test for linkage to regions or candidate genes that have been suggested on the basis of clinical findings (overlap with Smith-Lemli-Opitz syndrome (Donnai AJMG 38:741, 1987), a family history of proximal symphalangism (family B), and a patient with PHS-like findings and an unbalanced translocation (Kuller et al 43:746, 1992)). Linkage analysis demonstrates that all of these regions are excluded by LOD scores of <-2.0. We conclude that familial PHS is an autosomal dominant disorder with high penetrance and variable expressivity. Genome-wide linkage studies are under way.