X-Linked Acro-Gigantism (X-LAG) Due to Microduplications of Chromosome Xq26: A New Disorder and Implications for Acromegaly

Background: High growth hormone (GH) secretion is a rare condition that leads to gigantism in childhood and acromegaly in adults; the causes of gigantism and acromegaly are poorly understood. Aim of the study: To study the genetic defects underlying infantile gigantism and acromegaly. Patients and methods: We performed genomic and genetic studies in patients with gigantism (n=46), and then sequenced an implicated gene in an international cohort of acromegaly patients (n=248). In vitro functional studies were performed in rat somatomammotrope GH3 cells to assess the role of an identified genetic variant. Results: We detected by array-CGH a novel microduplication at chromosome Xq26 in two unrelated kindreds and twelve sporadic cases of various ethnic origins with infantile gigantism (n=16; 11 females). Two smallest regions of overlaps (SRO) were shared by the duplications; breakpoint junctions characterization revealed microhomology, suggesting a replicative mechanism for formation. The common duplicated genomic interval extends for approximately 500 Kb and contains four protein-coding genes. Only one of these genes, encoding a G-protein coupled receptor (GPCR) that strongly activates the cAMP signaling pathway was consistently over-expressed in patients’ pituitary lesions both at the RNA and protein level. We identified a recurrent variant in this gene in 4% of patients with acromegaly, mostly in tumors, whereas no pathogenic mutations were observed in the other three genes located within the SRO. When transfected into GH3 cells the mutation led to increased GH secretion and cell proliferation. Conclusions: We describe a previously unrecognized genomic disorder caused by Xq26 microduplication (X-LAG for X-linked acro-gigantism) and characterized by early-onset gigantism resulting from GH excess that can be transmitted as a dominant trait. The gene is a GPCR that is dosage-sensitive and over-expressed in patients’ pituitary lesions; it activates the cAMP pathway, whose mitogenic effects in pituitary somatotroph cells are well established; and a recurrent mutation is found in patients with sporadic acromegaly.