Irish giants: from myth to medicine.

The archetype of the 'Irish giant' in folklore appears to be rooted in historical individuals afflicted by pituitary gigantism. This review compiles and critically assesses the veracity of historical accounts, primarily from the late 17th to the early 20th century, for a group of individuals with gigantism that had Irish origins. Clinical and, in some cases, osteological data (e.g., Charles Byrne, Cornelius Magrath, and Patrick Cotter) confirm a diagnosis of pituitary gigantism, a rare disease that is caused by excess growth hormone secretion from a pituitary adenoma. In the pre-scientific era, the effects of the unopposed hormone excess resulted in extreme tall stature, debilitating morbidity, and usually premature death. This aligns with our modern understanding of the potential severity of hormonal excess and tumour growth in pituitary gigantism. The high concentration of cases in Ulster is explained by a founder germline pathogenic variant (c.910 C > T, p.(R304*)) in the AIP gene, that was identified in multiple contemporary families, later in the skeleton of Charles Byrne and most recently, among the Irish diaspora. Estimated to have arisen around 2500 years ago, this variant established a direct medical explanation for a regional phenomenon. In this review we provide a detailed compilation of historical Irish giants and discuss the evidence linking myth and folklore to the modern medical reality of pituitary gigantism as a rare, severe genetic disease.