Pituitary gigantism is a rare but important form of overgrowth due to GH/IGF-1 excess. The initial aim of the present research was to design and implement a comprehensive cohort study of the etiology, clinical diagnosis and management of this rare disease. This work describes the findings of an international collaborative study involving the largest pituitary gigantism population described to date (208 patients) from 47 centers across the globe to explore the specific characteristics of these patients and the genetic background of pituitary gigantism. Overall, the work undertaken has permitted us to identify the clinical phenotype and treatment outcomes in patients with pituitary gigantism; these features differ significantly from those in adult somatotropinoma patients with acromegaly. Patients with gigantism presented clear a male predominance (95%) and differ in their presentation based on gender, with females presenting significantly earlier than males. Increased somatic growth in pituitary gigantism is associated with an early onset form of GH/IGF-1 hypersecretion due to pituitary tumors that are highly resistant to treatment. These characteristics point to specific molecular mechanisms in pituitary tumor formation. Until recently, pituitary gigantism has been a well-known disease but poorly understood from genetic point of view. Underlying genetic causes have been studied comprehensively and identified in half of the cases in our large international series. While complex multi-organ syndromes (such as McCune-Albright syndrome (MAS), MEN1 and Carney Complex) counted only for rare cases of pituitary gigantism (7% in total), the most frequent genetic etiologies appear to be those leading to disease isolated to the pituitary, such as AIP mutations (29%) and X-linked acrogigantism syndrome (X-LAG) (10%). The latter is a new genetic form of infant-onset acrogigantism, occurring sporadically and in familial setting, which was described for the first time during the course of this work. X-LAG remains rare and only about 33 genetically confirmed cases have been published to date. X-LAG is a dramatically aggressive disorder affecting children from a very young age (usually during the first year), who are predominantly female (70%). Despite the very young age at disease onset, X-LAG patients develop large pituitary lesions (frequently mixed GH and prolactin secreting adenomas and/or hyperplasia) with extremely elevated hormonal levels. This contributes certainly to excessively rapid somatic growth leading to severe overgrowth. The remarkable phenotype of X-LAG syndrome is underlined by an unusual genetic mechanism; it is due to a microduplication on Xq26.3 including always GPR101 gene, whereas previously described genetic mechanisms in pituitary tumorigenesis are mainly triggered by a point mutation or deletions in a single gene. Additionally, a novel genetic technology (digital droplet PCR (ddPCR)) revealed that males with X-LAG syndrome can be mosaics for the GPR101 duplication, and as few as 16% of duplicated cells could lead to severe overgrowth. Many of the tallest giants in history had a clinical history that exactly mirrors this phenotype. The molecular diagnosis of X-LAG due to a duplication in GPR101 was made using paleogenetic extraction techniques in combination with modern ddPCR on DNA successfully isolated from the century-old remains of the historical case of The Giant Constantin (2.59m) who had autopsy findings of a pituitary adenoma. It can be considered as the tallest genetically proven case of gigantism available. It was also noted that more than 50% of cases remain genetically unexplained. Importantly, these genetic subgroups have statistically significant differences in terms of features at presentation/diagnosis, however all pituitary giants, including the genetically negative group, have aggressive clinical characteristics. Further studies were focused on the association of genetic events, in particular AIP mutations, with the aggressive phenotype of somatotropinomas that are resistant to conventional treatment. The clinical experience in patients with pituitary gigantism that have failed previous therapy with first generation somatostatin analogues, showed the role of other treatment options (pegvisomant, paseriotide) in hormonal and tumoral control in genetically negative and AIP mutated cases. A severe disease burden was highlighted in a comprehensive autopsy and genetic analysis in an adult male patient with a complex clinical profile of MAS including pituitary gigantism. The pathological findings and the presence of GNAS1 mutation in a mosaic state in different endocrine and non-endocrine tissues, combined with the clinical description of this case in the medical records, illustrated the challenges in treatment and consequences of disease activity. Crucially, the results derived from our large pituitary gigantism cohort and our further studies in specific genetically predisposed forms (such as X-LAG, AIP mutation– or MAS– related cases) pointed out that pituitary gigantism is a severe therapeutic challenge, requiring a multimodal treatment approach. However, one of the major findings of our research shows that early recognition and effective management in terms of sustained hormonal control and pituitary tumor shrinkage are essential for limiting the pathological effects on height and multi-organ disease burden.