Pituitary gigantism is a rare disorder caused by excess of GH/IGF-1 due to GH-secreting lesions, that occurs before epiphyseal closure leading to increased linear growth. These cases have more aggressive features of pituitary disease than sporadic acromegaly, including a younger age at disease onset and larger tumor size, and they can be challenging to treat. Over the past two decades several molecular defects that cause GH-secreting pituitary adenomas have been identified, including multiple endocrine neoplasia syndromes type 1 and 4, Carney complex, McCune-Albright syndrome, familial isolated pituitary adenoma (FIPA) and AIP mutations, pituitary adenoma with paraganglioma/pheochromocytoma, and the recently identified X-linked acrogigantism syndrome (X-LAG). About half of pituitary gigantism cases have genetic predisposition, and AIP mutations represent the most frequent genetic cause of pituitary gigantism (29%). X-LAG is a novel pediatric syndrome due to chromosome Xq26.3 microduplications involving GPR101. X-LAG can be caused by variable degrees of somatic mosaicism for GPR101 duplication in sporadic males. X-LAG accounts for 10% of pituitary gigantism cases and 80% of early-onset pediatric gigantism. Hypothalamic GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG, and in vitro studies showed that GHRH receptor antagonist can significantly reduce GH release. Besides sporadic cases, X-LAG represents a new genetic cause of non-AIP FIPA, transmission from affected mother to affected son was reported in 3 FIPA families. X-LAG is more frequent in females, and associated with early-onset pituitary disease (in most cases during the 1 year of life, and always before age of 5) and extremely accelerated linear growth. X-LAG is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Response to somatostatin analogs is poor and multimodal treatment is frequently required, including neurosurgery, GH receptor antagonist and radiotherapy, which however increase the risk of hypopituitarism.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology