GNAS mutation analyses and MS-MLPA assays are useful molecular tools for understanding the molecular bases and confirming the diagnosis of PHP and PPHP.
The term pseudohypoparathyroidism (PHP) refers to the different disorders that are caused by mutations within GNAS or upstream of this complex genetic locus.
Due to monoallelic expression, heterozygous GNAS mutations affecting either paternally or maternally derived transcripts cause different forms of pseudohypoparathyroidism (PHP), including autosomal-dominant PHP type Ib (AD-PHP1B) associated with loss of methylation (LOM) at exon A/B alone or sporadic PHP1B (sporPHP1B) associated with broad GNAS methylation changes.
The term pseudohypoparathyroidism (PHP) was coined to describe the clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by genetic and/or epigenetic alterations within or upstream of GNAS.
Pseudohypoparathyroidism is a rare genetic disorder characterised by end-organ resistance to parathyroid hormone due to a defect of the guanine nucleotide-binding protein alpha that simulates activity of the polypeptide 1 (GNAS) gene.
Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss-of-methylation (LOM) at exon A/B alone or at all maternally methylated GNAS exons.
Pseudohypoparathyroidism (PHP) is a rare endocrine disorder derived from the defective activation of the cAMP pathway by the parathyroid hormone secondary to GNAS molecular defects.
Patients with PHP 1a have heterozygous mutations within the exons of the maternal GNAS allele that encode Gα(s), whereas patients with PHP 1b have methylation defects in the GNAS locus that reduce transcription of Gα(s) from the maternal allele.
The patient displayed no other laboratory or physical abnormalities to suggest other GNAS-associated disorders of cutaneous ossification, including Albright's hereditary osteodystrophy or pseudohypoparathyroidism 1A, although a history of intrauterine growth restriction was troubling for progressive osseous heteroplasia.
Pseudohypoparathyroidism (PHP) is associated with compromised signal transductions via PTH receptor (PTH-R) and other G-protein-coupled receptors including GHRH-R. To date, while GH deficiency (GHD) has been reported in multiple patients with PHP-Ia caused by mutations on the maternally expressed GNAS coding regions and in two patients with sporadic form of PHP-Ib accompanied by broad methylation defects of maternally derived GNAS differentially methylated regions (DMRs), it has not been identified in a patient with an autosomal dominant form of PHP-Ib (AD-PHP-Ib) accompanied by an STX16 microdeletion and an isolated loss of methylation (LOM) at exon A/B-DMR.
Of the 408 polymorphic microsatellite markers examined, markers located on chromosome 20q13.3, the region containing GNAS1, demonstrated linkage to PHP lb.
Heterozygous GNAS inactivating mutations are known to induce pseudohypoparathyroidism type 1a when maternally inherited and pseudopseudohypoparathyroidism when paternally inherited.
Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia.
This observation suggests that: 1) the decreased expression of Galphas due to GNAS epimutations is not restricted to the renal tubule but may affect nonimprinted tissues like bone; 2) PHP-Ib is a heterogeneous disorder that should lead to studying GNAS epigenotype in patients with PHP and no mutation in GNAS exons 1-13, regardless of their physical features.
Pseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of hormones that activate Gsalpha, encoded by the imprinted GNAS gene.
The segregation of brachydactyly with PHP 1b in this family indicates that an imprinting defect in GNAS can lead to growth plate defects, including brachydactyly and Madelung deformity.