The Spectrum of Familial Pituitary Neuroendocrine Tumors

Hereditary pituitary tumorigenesis is seen in a relatively small proportion (around 5%) of patients with pituitary neuroendocrine tumors (PitNETs). The aim of the current review is to describe the main clinical and molecular features of such pituitary tumors associated with hereditary or familial characteristics, many of which have now been genetically identified. The genetic patterns of inheritance are classified into isolated familial PitNETs and the syndromic tumors. In general, the established genetic causes of familial tumorigenesis tend to present at a younger age, often pursue a more aggressive course, and are more frequently associated with growth hormone hypersecretion compared to sporadic tumors. The mostly studied molecular pathways implicated are the protein kinase A and phosphatidyl-inositol pathways, which are in the main related to mutations in the syndromes of familial isolated pituitary adenoma (FIPA), Carney complex syndrome, and X-linked acrogigantism. Another well-documented mechanism consists of the regulation of p27 or p21 proteins, with further acceleration of the pituitary cell cycle through the check points G1/S and M/G1, mostly documented in multiple endocrine neoplasia type 4. In conclusion, PitNETs may occur in relation to well-established familial germline mutations which may determine the clinical phenotype and the response to treatment, and may require family screening.