Journal of Endocrinological Investigation

, Volume 40, Issue 4, pp 347–356 | Cite as

Pseudohypoparathyroidism: one gene, several syndromes

  • O. Tafaj
  • H. JüppnerEmail author


Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several sites. GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Heterozygous inactivating mutations involving the maternal GNAS exons 1–13 cause PHP type Ia (PHP1A). Because of much reduced paternal Gsα expression in certain tissues, such as the proximal renal tubules, thyroid, and pituitary, there is little or no Gsα protein in the presence of maternal GNAS mutations, thus leading to PTH-resistant hypocalcemia and hyperphosphatemia. When located on the paternal allele, the same or similar GNAS mutations are the cause of PPHP. Besides biochemical abnormalities, patients affected by PHP1A show developmental abnormalities, referred to as Albrights hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who typically show no laboratory abnormalities. 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. LOM at exon A/B and the resulting biallelic expression of A/B transcripts reduces Gsα expression, thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, the most frequent disease variant, which remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).


Pseudohypoparathyroidism Pseudopseudohypoparathyroidism PHP1A PHP1B GNAS Stimulatory G protein Syntaxin 16 STX16 Albrights hereditary osteodystrophy 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

For this review article no studies with human participants or animal experimentation were performed by the two authors.

Informed consent

For this type of study formal consent is not required.


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© Italian Society of Endocrinology (SIE) 2016

Authors and Affiliations

  1. 1.Endocrine Unit, Department of MedicineMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Pediatric Nephrology Unit, Department of PediatricsMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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