Opitz G/BBB syndrome (OS) was first described in 1969 as two separate disorders, the G syndrome, and the BBB syndrome. Since that time, it has become apparent that the BBB and the G syndromes are in fact a single entity, now named the Opitz G/BBB syndrome. However, our recent molecular genetic mapping studies have shown that OS is an heterogeneous disorder, with loci at Xp22 and 22q. To determine if there are any discernible phenotypic differences between the X-linked and the autosomal dominant forms of OS, we have conducted a clinical study of the families who participated in the linkage analysis. In addition, we compared the clinical findings in the study families with those who have been reported in the literature. We found that anteverted nares and posterior pharyngeal cleft were seen only in X-linked families. However, all other manifestations of OS, such as hypertelorism, swallowing difficulties, hypospadias, and developmental delay, were seen in both groups. Therefore, while OS is heterogeneous, significant clinical overlap is present between the two groups, and it is presently impossible to assign a specific phenotype to the X-linked or the autosomal type of OS. Furthermore, we found that for individuals in our study families who carried the OS allele, the incidence of major abnormalities was lower than what is reported in the literature.