The early history of Pallister-Hall syndrome-Buried treasure of a sort

- Sentinal, unusual clinical findings are important in identifying additional cases of what is though to be a rare syndrome
- Careful family histories may identify mildly affected individuals and point to the possible mode of inheritance
- If the family history reflects single gene inheritance, the gene may be identified by gene exome or whole genome sequencing.
- Single gene disorder relation to another disorder needs clarification of the phenotype/genotype relation & molecular pathways.
- Some clinicians' curiosity may lead them in usual directions-like into the ground.

Pallister-Hall syndrome was initially recognized under fairly unique circumstances involving exhumation of the very first case. The first two cases had dramatic and unusual features including a hypothalamic hamartoblastoma, imperforate anus, an unusual type of polydactyly with the extra digit being central, hypopituitarism with secondary hypoadrenalism, and lethality after birth (probably due to hypoadrenalism). Within a short time frame, four additional cases were identified. As the full spectrum and variability of anomalies was recognized, it became clear that it was not such a rare disorder. Shortly after familial cases were recognized, the responsible gene was identified at GLI3. However, since other different conditions also involved GLI3, elaborating the domains of the gene and the types of mutations needed to be defined in order to have a clear correlation of the genotype-phenotype relations.