Mechanism of Pseudopseudohypoparathyroidism
Pseudopseudohypoparathyroidism (PPHP) results from paternally inherited heterozygous inactivating mutations in the GNAS gene encoding the Gsα protein, causing the physical features of Albright hereditary osteodystrophy (AHO) without hormone resistance due to tissue-specific genomic imprinting. 1, 2, 3
Genetic Basis
PPHP is caused by heterozygous inactivating mutations within the GNAS gene exons that encode the alpha-subunit of the stimulatory G protein (Gsα), which is essential for parathyroid hormone (PTH) and other hormone signaling 4, 5
The same GNAS mutations that cause pseudohypoparathyroidism type Ia (PHP-Ia) when maternally inherited will cause PPHP when paternally inherited 3, 5
Multiple different mutation types have been identified, including deletions (p.Asp189_Tyr190delinsMetfxX14), frameshifts (p.Val117fsX23, p.Tyr190CysfsX19), and splicing mutations (c.659 + 1G>A) 2
Imprinting Mechanism Explaining the Phenotype
The critical distinction between PPHP and PHP-Ia is explained by parent-of-origin-specific (genomic imprinting) expression of Gsα in hormone-responsive tissues 4, 5
In renal proximal tubules and certain other endocrine target tissues, Gsα is expressed predominantly or exclusively from the maternal allele due to tissue-specific imprinting 4, 5
When the GNAS mutation is inherited from the father (PPHP), the paternal allele is already silenced by imprinting in these tissues, so the functional maternal allele remains intact and hormone signaling proceeds normally 5
When the same mutation is inherited from the mother (PHP-Ia), the functional maternal allele is disrupted while the paternal allele remains silenced, resulting in marked reduction of Gsα levels and hormone resistance 4
Clinical Manifestations
Patients with PPHP exhibit the somatic features of Albright hereditary osteodystrophy (AHO), including short stature, round facies, subcutaneous ossifications, brachydactyly, and obesity 1, 2, 3
Unlike PHP-Ia patients, those with PPHP do not develop resistance to PTH, thyroid-stimulating hormone (TSH), or other hormones, maintaining normal calcium homeostasis and thyroid function 3, 5
Subcutaneous calcification can appear as an early manifestation of AHO, sometimes presenting as early as 7 months of age 2
Haploinsufficiency Component
The combination of tissue-specific genomic imprinting and haploinsufficiency explains why PPHP patients have AHO features despite lacking hormone resistance 5
In tissues where Gsα is expressed from both alleles (non-imprinted tissues), having only one functional copy (50% Gsα activity) is sufficient to cause the developmental abnormalities characteristic of AHO 5
This haploinsufficiency model also explains why not all Gs-mediated hormone actions are affected equally in PHP-Ia, as different tissues have varying degrees of imprinting 5