Discovering X-linked acrogigantism: a new infant-onset overgrowth syndrome

2017

Challenge

Pituitary gigantism is a very rare condition wherein a tumor on the pituitary gland causes over-secretion of growth hormone, leading to excessive body growth. About half the cases of gigantism are of unknown genetic origin. Therefore, understanding the underlying genetic defects is extremely important for providing correct diagnosis and treatment.

Advance

IRP researchers led by Constantine A. Stratakis, M.D., D(med).Sci., discovered a new syndrome of early childhood–onset gigantism that occurs when a small portion of the X chromosome, including the GPR101 gene, is abnormally duplicated. This new condition, which they named X-linked acrogigantism (X-LAG), explains about 10% of all cases of gigantism and as many as 80% of pre-pubertal cases. The team extensively examined the clinical and hormonal symptoms of X-LAG, as well as patients’ responses to therapy. Finally, the investigators characterized the culprit gene, GPR101, at the molecular level.

Impact

The discovery and characterization of X-LAG offers pediatricians the appropriate diagnostic tools to recognize the disease early in life, initiate treatment, and provide genetic counseling. Moreover, the findings offer the opportunity to study a new important pathway involved in the central regulation of human growth.

Publications

Trivellin G, Bjelobaba I, Daly AF, Larco DO, Palmeira L, Faucz FR, Thiry A, Leal LF, Rostomyan L, Quezado M, Schernthaner-Reiter MH, Janjic M, Villa C, Wu TJ, Stojilkovic SS, Beckers A, Feldman B, Stratakis CA (2016). Characterization of GPR101 transcript structure and expression patterns. J Mol Endocrinol. 57(2):97-111.

Beckers A, Lodish MB, Trivellin G, Rostomyan L, Lee M, Faucz FR, Yuan B, Choong CS, Caberg JH, Verrua E, Naves LA, Cheetham TD, Young J, Lysy PA, Petrossians P, Cotterill A, Shah NS, Metzger D, Castermans E, Ambrosio MR, Villa C, Strebkova N, Mazerkina N, Gaillard S, Barra GB, Casulari LA, Neggers SJ, Salvatori R, Jaffrain-Rea ML, Zacharin M, Lecumberri Santamaria B, Zacharieva S, Lim EM, Mantovani G, Zatelli MC, Collins MT, Bonneville JF, Quezado M, Chittiboina P, Oldfield EH, Bours V, Liu P, de Herder WW, Pellegata N, Lupski JR, Daly AF, Stratakis CA (2015). X-linked acrogigantism (X-LAG) syndrome: clinical profile and therapeutic responses. Endocr Relat Cancer. 22(3):353-67.

Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, Castermans E, Villa C, Dimopoulos A, Chittiboina P, Xekouki P, Shah N, Metzger D, Lysy PA, Ferrante E, Strebkova N, Mazerkina N, Zatelli MC, Lodish M, Horvath A, de Alexandre RB, Manning AD, Levy I, Keil MF, de la Luz Sierra M, Palmeira L, Coppieters W, Georges M, Naves LA, Jamar M, Bours V, Wu TJ, Choong CS, Bertherat J, Chanson P, Kamenický P, Farrell WE, Barlier A, Quezado M, Bjelobaba I, Stojilkovic SS, Wess J, Costanzi S, Liu P, Lupski JR, Beckers A, Stratakis CA (2014). Gigantism and acromegaly due to Xq26 microduplications and GPR101 defects. N Engl J Med. 371(25):2363-74.