The two main subtypes of pseudohypoparathyroidism (PHP), PHP-Ia and -Ib, are caused
by mutations in GNAS exons 1–13 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO),
together with end-organ resistance to the action of different hormones that activate
the Gs-coupled pathways, primarily PTH, TSH, gonadotropins, and GHRH. In PHP-Ib patients
AHO is classically absent, Gsα activity in erythrocytes and fibroblast is normal and
hormone resistance is limited to PTH and TSH, the latter being essentially always
subclinical. This disorder is caused by the disruption of long-range imprinting control
elements in GNAS locus. In particular, the most consistent defect is the loss of imprinting at the
exon A/B differenzially methylated region (DMR), with consequent decreased Gsα transcription
in tissues where this protein is derived from the maternal allele only. The familial form of the disease (AD-PHP-Ib) is typically associated with an isolated
loss of imprinting at the exon A/B DMR due to microdeletions disrupting the upstream
STX16 gene. In addition, deletions removing the entire NESP55 DMR, located within
GNAS, have been identified in some AD-PHP-Ib kindreds in whom affected individuals show
loss of all the maternal GNAS imprints. Conversely, most sporadic PHP-Ib cases have GNAS imprinting abnormalities that involve multiple DMRs, but the genetic lesion underlying
these defects remains to be discovered. Recently, methylation defects have been detected
in a subset of patients with PHP-Ia and variable degrees of AHO, indicating a molecular
overlap between the two forms. Imprinting defects do not seem to be associated with
the severity of AHO neither with specific AHO signs.
In conclusion, the latest findings of frequent GNAS imprinting defects in patients with major clinical and biochemical differences in
respect with classical PHP-Ib, further confirm the existence of an overlap between
the molecular and clinical features of PHP-Ia and PHP-Ib, and highlight the necessity
of a new clinical classification of these diseases, taking into account the recent
knowledge on the molecular basis underlying these defects.
