Genetic causes of acromegalia: a narrative review
PDF (Español (España))
xhtml (Español (España))


multiple endocrine neoplasia
Carney complex
fibrous dysplasia polyostotic

How to Cite

Román González , A. ., Padilla Zambrano , H. S., López Montoya, V., Gutiérrez , J., & Builes-Barrera , C. A. (2022). Genetic causes of acromegalia: a narrative review. Revista Colombiana De Endocrinología, Diabetes &Amp; Metabolismo, 9(2).


Context:  Acromegaly is caused in most cases by growth hormone-producing pituitary tumors. These tumors usually occur in a sporadic context or rarely, associated with a hereditary syndrome. In recent years, the landscape of family mutations and syndromes associated with acromegaly and gigantism has expanded.

Objective: The aim of this review focus on the current knowledge of the genetic bases causing familial acromegaly.

Methods: Medical electronic databases and endocrine textbooks were reviewed. Genetic causes of acromegaly are presented.

Results: The genetic causes of acromegaly are diseases such as Carney Complex, multiple endocrine neoplasia type 1, familial isolated pituitary tumors (FIPA), X-linked acrogigantism (XLAG), familial pituitary adenomas with pheochromocytoma/paraganglioma (3P), McCune Albright syndrome and neurofibromatosis.

Conclusions: Multiple endocrine neoplasia should be rule out in all cases of acromegaly though calcium and parathyroid hormone measurement. All patients should have a complete family history ruling out FIPA. Also, in patients presenting at a young age other genetic causes of acromegaly must be sought.
PDF (Español (España))
xhtml (Español (España))


Colao A, Grasso LFS, Giustina A, Melmed S, Chanson P, Pereira AM, et al. Acromegaly. Nat Rev Dis Prim. 2019 Mar;5(1):20.

Hannah-Shmouni F, Trivellin G, Stratakis CA. Genetics of gigantism and acromegaly. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc. 2016;30–31:37–41.

Ramírez-Rentería C, Hernández-Ramírez LC, Portocarrero-Ortiz L, Vargas G, Melgar V, Espinosa E, et al. AIP mutations in young patients with acromegaly and the Tampico Giant: the Mexican experience. Endocrine. 2016 Aug;53(2):402–11.

Hozumi K, Fukuoka H, Odake Y, Takeuchi T, Uehara T, Sato T, et al. Acromegaly caused by a somatotroph adenoma in patient with neurofibromatosis type 1. Endocr J. 2019 Oct;66(10):853–7.

Burton T, Le Nestour E, Neary M, Ludlam WH. Incidence and prevalence of acromegaly in a large US health plan database. Pituitary. 2016 Jun;19(3):262–7.

Gadelha MR, Kasuki L, Korbonits M. The genetic background of acromegaly. Pituitary. 2017 Feb;20(1):10–21.

Katznelson L, Atkinson JLD, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly--2011 update. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2011;17 Suppl 4:1–44.

Valdes-Socin H, Poncin J, Stevens V, Stevenaert A, Beckers A. Familial isolated pituitary adenomas not linked to somatic MEN-1 mutations. Follow-up of 27 patients. Ann Endocrinol. 2000;61:301.

Tahir A, Chahal HS, Korbonits M. Molecular genetics of the aip gene in familial pituitary tumorigenesis. Prog Brain Res. 2010;182:229–53.

Caimari F, Korbonits M. Novel Genetic Causes of Pituitary Adenomas. Vol. 22, Clinical cancer research?: an official journal of the American Association for Cancer Research. United States; 2016. p. 5030–42.

Marques P, Korbonits M. Genetic Aspects of Pituitary Adenomas. Endocrinol Metab Clin North Am. 2017 Jun;46(2):335–74.

Beckers A, Daly AF. The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol. 2007 Oct;157(4):371–82.

Hernández-Ramírez LC, Gabrovska P, Dénes J, Stals K, Trivellin G, Tilley D, et al. Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers. J Clin Endocrinol Metab. 2015 Sep;100(9):E1242-54.

Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med. 2014 Dec;371(25):2363–74.

Daly AF, Vanbellinghen J-F, Khoo SK, Jaffrain-Rea M-L, Naves LA, Guitelman MA, et al. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab. 2007 May;92(5):1891–6.

Daly AF, Beckers A. Update on the treatment of pituitary adenomas: familial and genetic considerations. Acta Clin Belg. 2008;63(6):418–24.

Daly AF, Jaffrain-Rea M-L, Ciccarelli A, Valdes-Socin H, Rohmer V, Tamburrano G, et al. Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab. 2006 Sep;91(9):3316–23.

Igreja S, Chahal HS, King P, Bolger GB, Srirangalingam U, Guasti L, et al. Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum Mutat. 2010 Aug;31(8):950–60.

Daly AF, Tichomirowa MA, Petrossians P, Heliövaara E, Jaffrain-Rea M-L, Barlier A, et al. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab. 2010 Nov;95(11):E373-83.

Trivellin G, Korbonits M. AIP and its interacting partners. J Endocrinol. 2011 Aug;210(2):137–55.

Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science. 2006 May;312(5777):1228–30.

Araujo PB, Kasuki L, de Azeredo Lima CH, Ogino L, Camacho AHS, Chimelli L, et al. AIP mutations in Brazilian patients with sporadic pituitary adenomas: a single-center evaluation. Endocr Connect. 2017 Nov;6(8):914–25.

Daly AF, Beckers A. Familial isolated pituitary adenomas (FIPA) and mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocrinol Metab Clin North Am. 2015 Mar;44(1):19–25.

Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernández-Ramírez LC, et al. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathol Commun. 2016 Jun;4(1):56.

Chahal HS, Stals K, Unterländer M, Balding DJ, Thomas MG, Kumar A V, et al. AIP mutation in pituitary adenomas in the 18th century and today. N Engl J Med. 2011 Jan;364(1):43–50.

Iacovazzo D, Korbonits M. Gigantism: X-linked acrogigantism and GPR101 mutations. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc. 2016;30–31:64–9.

Daly AF, Lysy PA, Desfilles C, Rostomyan L, Mohamed A, Caberg J-H, et al. GHRH excess and blockade in X-LAG syndrome. Endocr Relat Cancer. 2016 Mar;23(3):161–70.

Thakker R V., Newey PJ, Walls G V., Bilezikian J, Dralle H, Ebeling PR, et al. Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep 1;97(9):2990–3011.

Larsson C, Skogseid B, Öberg K, Nakamura Y, Nordenskjöld M. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature. 1988 Mar;332(6159):85–7.

Lemos MC, Thakker R V. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008 Jan;29(1):22–32.

Turner JJO, Christie PT, Pearce SHS, Turnpenny PD, Thakker R V. Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1). Hum Mutat. 2010 Jan;31(1):E1089–101.

de Laat JM, van der Luijt RB, Pieterman CRC, Oostveen MP, Hermus AR, Dekkers OM, et al. MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. BMC Med. 2016 Dec 15;14(1):182.

Le Bras M, Leclerc H, Rousseau O, Goudet P, Cuny T, Castinetti F, et al. Pituitary adenoma in patients with multiple endocrine neoplasia type 1: a cohort study. Eur J Endocrinol. 2021 Dec 1;185(6):863–73.

Cohen-Cohen S, Brown DA, Himes BT, Wheeler LP, Ruff MW, Major BT, et al. Pituitary adenomas in the setting of multiple endocrine neoplasia type 1: a single-institution experience. J Neurosurg. 2021 Apr;134(4):1132–8.

Vergès B, Boureille F, Goudet P, Murat A, Beckers A, Sassolas G, et al. Pituitary Disease in MEN Type 1 (MEN1): Data from the France-Belgium MEN1 Multicenter Study. J Clin Endocrinol Metab. 2002 Feb;87(2):457–65.

Garby L, Caron P, Claustrat F, Chanson P, Tabarin A, Rohmer V, et al. Clinical Characteristics and Outcome of Acromegaly Induced by Ectopic Secretion of Growth Hormone-Releasing Hormone (GHRH): A French Nationwide Series of 21 Cases. J Clin Endocrinol Metab. 2012 Jun 1;97(6):2093–104.

Borson-Chazot F, Garby L, Raverot G, Claustrat F, Raverot V, Sassolas G. Acromegaly induced by ectopic secretion of GHRH: A review 30 years after GHRH discovery. Ann Endocrinol (Paris). 2012 Dec;73(6):497–502.

Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab. 2009 May;94(5):1826–34.

Sambugaro S, Di Ruvo M, Ambrosio MR, Pellegata NS, Bellio M, Guerra A, et al. Early onset acromegaly associated with a novel deletion in CDKN1B 5’UTR region. Endocrine. 2015 May;49(1):58–64.

Carney JA, Gordon H, Carpenter PC, Shenoy B V, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore). 1985 Jul;64(4):270–83.

Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab. 2001 Sep;86(9):4041–6.

Kamilaris CDC, Faucz FR, Voutetakis A, Stratakis CA. Carney Complex. Exp Clin Endocrinol diabetes Off journal, Ger Soc Endocrinol [and] Ger Diabetes Assoc. 2019 Feb;127(2–03):156–64.

Correa R, Salpea P, Stratakis CA. Carney complex: an update. Eur J Endocrinol. 2015 Oct;173(4):M85-97.

Bossis I, Stratakis CA. Minireview: PRKAR1A: normal and abnormal functions. Endocrinology. 2004 Dec;145(12):5452–8.

Bosco Schamun MB, Correa R, Graffigna P, de Miguel V, Fainstein Day P. Revisión del complejo de Carney: Aspectos genéticos. Endocrinol Diabetes y Nutr. 2018 Jan;65(1):52–9.

Boikos SA, Stratakis CA. Carney complex: the first 20 years. Curr Opin Oncol. 2007 Jan;19(1):24–9.

Schernthaner-Reiter MH, Trivellin G, Stratakis CA. MEN1, MEN4, and Carney Complex: Pathology and Molecular Genetics. Neuroendocrinology. 2016;103(1):18–31.

Cuny T, Mac TT, Romanet P, Dufour H, Morange I, Albarel F, et al. Acromegaly in Carney complex. Pituitary. 2019 Oct;22(5):456–66.

Boikos SA, Stratakis CA. Pituitary pathology in patients with Carney Complex: growth-hormone producing hyperplasia or tumors and their association with other abnormalities. Pituitary. 2006;9(3):203–9.

Pack SD, Kirschner LS, Pak E, Zhuang Z, Carney JA, Stratakis CA. Genetic and histologic studies of somatomammotropic pituitary tumors in patients with the “complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas” (Carney complex). J Clin Endocrinol Metab. 2000 Oct;85(10):3860–5.

Watson JC, Stratakis CA, Bryant-Greenwood PK, Koch CA, Kirschner LS, Nguyen T, et al. Neurosurgical implications of Carney complex. J Neurosurg. 2000 Mar;92(3):413–8.

Giraldi FP, Fatti LM, Bertola G, Balza G, Lavezzi E, Pesce S, et al. Carney’s complex with acromegaly as the leading clinical condition. Clin Endocrinol (Oxf). 2007 Sep 18;070920202621001-???

Rojo Álvaro J, Martínez de Esteban JP, Pineda Arribas JJ, Ollero García-Agulló MD, Munárriz Alcuaz P. Acromegalia en paciente afecto de complejo de Carney. Endocrinol y Nutr. 2013 May;60(5):277–8.

Lonser RR, Mehta GU, Kindzelski BA, Ray-Chaudhury A, Vortmeyer AO, Dickerman R, et al. Surgical Management of Carney Complex-Associated Pituitary Pathology. Neurosurgery. 2017 May;80(5):780–6.

Gorman P, Hewer RL. Stroke due to atrial myxoma in a young woman with co-existing acoustic neuroma and pituitary adenoma. Vol. 48, Journal of neurology, neurosurgery, and psychiatry. 1985. p. 718–9.

Heck A, Ringstad G, Fougner SL, Casar-Borota O, Nome T, Ramm-Pettersen J, et al. Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clin Endocrinol (Oxf). 2012 Jul;77(1):72–8.

Potorac I, Beckers A, Bonneville J-F. T2-weighted MRI signal intensity as a predictor of hormonal and tumoral responses to somatostatin receptor ligands in acromegaly: a perspective. Pituitary. 2017 Feb;20(1):116–20.

Dwight T, Mann K, Benn DE, Robinson BG, McKelvie P, Gill AJ, et al. Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. J Clin Endocrinol Metab. 2013 Jun;98(6):E1103-8.

Dénes J, Swords F, Rattenberry E, Stals K, Owens M, Cranston T, et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metab. 2015 Mar;100(3):E531-41.

Xekouki P, Brennand A, Whitelaw B, Pacak K, Stratakis CA. The 3PAs: An Update on the Association of Pheochromocytomas, Paragangliomas, and Pituitary Tumors. Horm Metab Res = Horm und Stoffwechselforsch = Horm Metab. 2019 Jul;51(7):419–36.

Xekouki P, Pacak K, Almeida M, Wassif CA, Rustin P, Nesterova M, et al. Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH? J Clin Endocrinol Metab. 2012 Mar;97(3):E357-66.

O’Toole SM, Dénes J, Robledo M, Stratakis CA, Korbonits M. 15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr Relat Cancer. 2015 Aug;22(4):T105–22.

Xekouki P, Szarek E, Bullova P, Giubellino A, Quezado M, Mastroyannis SA, et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metab. 2015 May;100(5):E710-9.

López-Jiménez E, de Campos JM, Kusak EM, Landa I, Leskelä S, Montero-Conde C, et al. SDHC mutation in an elderly patient without familial antecedents. Clin Endocrinol (Oxf). 2008 Dec;69(6):906–10.

Lemelin A, Lapoirie M, Abeillon J, Lasolle H, Giraud S, Philouze P, et al. Pheochromocytoma, paragangliomas, and pituitary adenoma: An unusual association in a patient with an SDHD mutation. Case report. Medicine (Baltimore). 2019 Jul;98(30):e16594.

Guerrero-Pérez F, Fajardo C, Torres Vela E, Giménez-Palop O, Lisbona Gil A, Martín T, et al. 3P association (3PAs): Pituitary adenoma and pheochromocytoma/paraganglioma. A heterogeneous clinical syndrome associated with different gene mutations. Eur J Intern Med. 2019 Nov;69:14–9.

Daly AF, Castermans E, Oudijk L, Guitelman MA, Beckers P, Potorac I, et al. Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions. Vol. 25, Endocrine-related cancer. England; 2018. p. L37–42.

Gadelha MR, Trivellin G, Hernández Ramírez LC, Korbonits M. Genetics of pituitary adenomas. Front Horm Res. 2013;41:111–40.

Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet J Rare Dis. 2008 Dec 19;3(1):12.

Salpea P, Stratakis CA. Carney complex and McCune Albright syndrome: an overview of clinical manifestations and human molecular genetics. Mol Cell Endocrinol. 2014 Apr;386(1–2):85–91.

Salenave S, Boyce AM, Collins MT, Chanson P. Acromegaly and McCune-Albright syndrome. J Clin Endocrinol Metab. 2014 Jun;99(6):1955–69.

Akintoye SO, Chebli C, Booher S, Feuillan P, Kushner H, Leroith D, et al. Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome. J Clin Endocrinol Metab. 2002 Nov;87(11):5104–12.

Bizzarri C, Bottaro G. Endocrine implications of neurofibromatosis 1 in childhood. Horm Res Paediatr. 2015;83(4):232–41.

Checa Garrido A, del Pozo Picó C. Acromegalia y neurofibromatosis tipo 1. ¿Es casual la asociación entre ambas entidades? Endocrinol y Nutr. 2013 Mar;60(3):144–5.

Cambiaso P, Galassi S, Palmiero M, Mastronuzzi A, Del Bufalo F, Capolino R, et al. Growth hormone excess in children with neurofibromatosis type-1 and optic glioma. Am J Med Genet A. 2017 Sep;173(9):2353–8.

Josefson J, Listernick R, Fangusaro JR, Charrow J, Habiby R. Growth hormone excess in children with neurofibromatosis type 1-associated and sporadic optic pathway tumors. J Pediatr. 2011 Mar;158(3):433–6.

Hannah-Shmouni F, Stratakis CA. Growth hormone excess in neurofibromatosis 1. Vol. 21, Genetics in medicine?: official journal of the American College of Medical Genetics. United States; 2019. p. 1254–5.

García WR, Cortes HT, Romero AF. Pituitary gigantism: a case series from Hospital de San José (Bogotá, Colombia). Arch Endocrinol Metab. 2019 Jul 11;

Castellanos-Bueno R, Abreu-Lomba A, Buitrago-Gómez N, Patiño-Arboleda M, Pantoja-Guerrero D, Valenzuela-Rincón A, et al. Clinical and epidemiological characteristics, morbidity and treatment based on the registry of acromegalic patients in Colombia: RAPACO. Growth Horm IGF Res. 2021 Oct;60–61:101425.

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Copyright (c) 2022 Revista Colombiana de Endocrinología, Diabetes & Metabolismo




Download data is not yet available.