Genome architecture in endocrine diseases: X-linked acrogigantism (X-LAG) syndrome

X-linked acrogigantism (X-LAG) is a rare disease that represents a severe form of pituitary gigantism characterized by early-onset growth hormone (GH), insulin-like growth factor 1 (IGF1) and prolactin excess. X-LAG is associated with duplications involving the gene GPR101 on chromosome Xq26.3. Clinically, X-LAG manifests in infancy, with a median age at onset of 18 months, presenting as rapid linear growth, acral enlargement, and large pituitary macroadenomas. While predominantly a sporadic disease affecting females through constitutional duplications, somatic mosaicism is found in sporadic male cases. Three familial cases of X-LAG have been described. Management is difficult due to the young age of affected patients and the relative resistance of GH excess to somatostatin analogs. Multimodal therapy, including neurosurgery and medical therapy such as pegvisomant, is often required to achieve hormonal control and limit final adult height. Unlike other genetic forms of pituitary tumorigenesis that are due to sequence-based mutations, X-LAG is caused by structural changes in 3D genome architecture. Specifically, microduplications on chromosome Xq26.3 disrupt a topologically associating domain (TAD) containing GPR101. This process facilitates the formation of a "neoTAD", where the GPR101 promoter is driven by ectopic enhancers, primarily an intronic enhancer located within the VGLL1 gene, leading to massive pituitary upregulation of this constitutively active receptor and GH excess. X-LAG is an example of how novel disease mechanisms can explain the molecular dysregulation behind rare and difficult to manage endocrine pathologies.