All sporadic and some familial PHP-Ib cases show epigenetic defects at one or more GNAS DMRs in addition to the exon A/B DMR [63, 89]. These defects often consist of a loss of imprinting at exon A/B, exon XL, and the promoter of the antisense transcript and a gain of imprinting at exon NESP55. Two unrelated familial cases with such GNAS imprinting abnormalities have been shown to carry maternally inherited deletions of the entire NESP55 DMR including exons 3 and 4 of the antisense transcript [165], revealing the putative location of another control element required for the imprinting of the entire maternal GNAS allele (Fig. 4). The presence of similarly large deletions at the NESP55 DMR has been excluded in a number of sporadic PHP-Ib cases [165].
