Pituitary gigantism occurs due to hypersecretion of GH and insulin-like growth factor-1 (IGF-1) in children and adolescents before the closure of epiphyseal growth plates. This hormonal disorder is usually due to an adenoma or hyperplasia of the anterior pituitary gland and like other tumoral conditions in children often has a genetic background. Recently we demonstrated that a genetic predisposition is present in just under half of cases of pituitary gigantism. The best recognized causes are aryl hydrocarbon receptor interacting protein (AIP) gene mutations occurring sporadically or as familial isolated pituitary adenomas (FIPA), McCune Albright syndrome, and Carney Complex. In addition, we recently discovered and characterized a novel cause of pituitary gigantism, termed X-linked acrogigantism (X-LAG) syndrome. This condition differs from other forms of pituitary gigantism as it occurs at a significantly younger age and generally presents in the first year of life. It is associated with marked overgrowth due to GH, IGF-1 and often prolactin hypersecretion from a pituitary adenoma and or hyperplasia. Recent evidence suggests that X-LAG syndrome may originate from a central (e.g. hypothalamic) source of GHRH dysregulation. Patients with X-LAG syndrome have been shown to have a microduplication on chromosome Xq26.3 that includes the gene GPR101.
This gene encodes for an orphan GPCR that is highly expressed in the hypothalamus and in various areas of the brain. Adenomas/hyperplasia from patients with X-LAG syndrome over-express GPR101 both at the RNA and protein level, indicating that this receptor represents a novel pathway for regulation of growth signals. X-LAG syndrome is very challenging to treat as it gives rise to very marked hormonal excess and large pituitary adenomas in young children. Control is challenging but necessary as if left uncontrolled, chronic GH hypersecretion can lead to extreme gigantism. Standard somatostatin analog therapy is usually not effective and a combination of radical surgery plus pegivisomant may be required to halt overgrowth. Even small residual tumor remnants appear capable of inducing acromegaly in X-LAG syndrome patients, 40 to 50 years after initial disease onset. Diagnosis of X-LAG syndrome has important clinical genetic implications as the microduplication can be transmitted from affected parent to child in the setting of rare FIPA families.