The purpose of this study is to explore the phenotypic spectrum observed in individuals and between families with confirmed variants in the T-Box Transcription Factor 22 gene (TBX22). Pathogenic variants in TBX22 have been identified in individuals with classic X-linked cleft palate (CPX) and also in Abruzzo-Erickson Syndrome (ABERS). We compare the phenotypic features of a newly suspected family with ABERS to those of the original family with ABERS to help determine if family-specific pathogenic variants in TBX22 are the cause of ABERS. Furthermore, we discuss possible mechanisms of action of the identified TBX22 variants. We conducted an observational case series in a new family (Family B) suspected of having ABERS, and a retrospective review of participants in the original family with ABERS (Family A), as described by Abruzzo and Erickson (1977). Thirteen individuals from two different families were included in this case series. As previously reported in 2013, DNA samples from four individuals in Family A were screened for variants in TBX22, and each was found to carry the same unique pathogenic variant. Five individuals from Family B were screened for variants in TBX22, and the four with abnormal features were found to be positive for a new pathogenic variant; however, the variant segregating in this family differed from the one present in Family A. Despite this, there was considerable overlap between Family A and Family B in phenotypic features. Thus, we hypothesize that gain-of-function pathogenic variants in TBX22 are the probable cause of ABERS in both Family A and Family B.