PHP-Ib cases [89, 160]. Based on these findings, the genetic mutation responsible for PHP-Ib is thought to disrupt an imprinting regulatory element of GNAS. The most frequent mutation, identified thus far in more than 30 unrelated kindreds, is a unique 3-kb microdeletion located about 220 kb upstream of exon A/B [160-163] (Fig. 4). Flanked by two 391-bp repeats, the 3-kb microdeletion removes exons 4-6 of STX16, the gene encoding syntaxin-16. The second mutation is a 4.4-kb microdeletion that overlaps with the former and removes STX16 exons 2-4; this mutation, unlike the 3-kb microdeletion, has been found in only one kindred thus far [164]. These mutations cause disease only after maternal inheritance, and each affected individual carrying either of these mutations displays an isolated loss of exon A/B imprinting, thereby indicating that the mutations disrupt a cis-acting element that controls imprinting at the exon A/B DMR [160, 164]. This element may lie within the 1.3-kb region where the two deletions overlap. The overlapping region comprises exon 4, which is evolutionarily conserved and lies within a small CpG-rich region that lacks differential methylation [160]. It is also possible that the identified deletions independently disrupt a large control element that spans STX16. On
