PHP-Ib is often sporadic, but a number of familial cases have also been described. A careful analysis of these pedigrees has revealed that the PTH resistance in PHP-Ib develops only if the genetic defect is inherited from a female carrier [158], i.e. the mode of inheritance is identical to that observed for hormone resistance in PHP-Ia. Genetic linkage studies using some of these kindreds have mapped the genetic defect to a region of chromosome 20q that comprises the GNAS locus [158, 159]. Moreover, most PHP-Ib patients exhibit GNAS imprinting defects [63, 89]. Although these defects involve multiple GNAS DMRs in some cases, the most consistent defect is a loss of imprinting at the A/B DMR, i.e. loss of methylation at the A/B promoter and exon combined with biallelic A/B expression, which appears to be an isolated defect in most familial 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
