Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

J Endocrinol. 2019 Feb 1;240(2):R21-R45. doi: 10.1530/JOE-18-0446.


While 95% of pituitary adenomas arise sporadically without a known inheritable predisposing mutation, in about 5% of the cases they can arise in a familial setting, either isolated (familial isolated pituitary adenoma or FIPA) or as part of a syndrome. FIPA is caused, in 15-30% of all kindreds, by inactivating mutations in the AIP gene, encoding a co-chaperone with a vast array of interacting partners and causing most commonly growth hormone excess. While the mechanisms linking AIP with pituitary tumorigenesis have not been fully understood, they are likely to involve several pathways, including the cAMP-dependent protein kinase A pathway via defective G inhibitory protein signalling or altered interaction with phosphodiesterases. The cAMP pathway is also affected by other conditions predisposing to pituitary tumours, including X-linked acrogigantism caused by duplications of the GPR101 gene, encoding an orphan G stimulatory protein-coupled receptor. Activating mosaic mutations in the GNAS gene, coding for the Gα stimulatory protein, cause McCune-Albright syndrome, while inactivating mutations in the regulatory type 1α subunit of protein kinase A represent the most frequent genetic cause of Carney complex, a syndromic condition with multi-organ manifestations also involving the pituitary gland. In this review, we discuss the genetic and molecular aspects of isolated and syndromic familial pituitary adenomas due to germline or mosaic mutations, including those secondary to AIP and GPR101 mutations, multiple endocrine neoplasia type 1 and 4, Carney complex, McCune-Albright syndrome, DICER1 syndrome and mutations in the SDHx genes underlying the association of familial paragangliomas and phaeochromocytomas with pituitary adenomas.

Keywords: genetics; mutation; pituitary; pituitary adenoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenoma / genetics*
  • Adenoma / metabolism
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • Genetic Predisposition to Disease / genetics
  • Germ-Line Mutation*
  • Growth Hormone-Secreting Pituitary Adenoma / genetics*
  • Growth Hormone-Secreting Pituitary Adenoma / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mosaicism*
  • Pituitary Neoplasms / genetics*
  • Pituitary Neoplasms / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism


  • GPR101 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Receptors, G-Protein-Coupled
  • aryl hydrocarbon receptor-interacting protein
  • GTP-Binding Protein alpha Subunits, Gs

Supplementary concepts

  • Pituitary Adenoma, Familial Isolated