Modern views on the genetic determinism of GH-secreting pituitary adenomas (literature review and own data)

Main Article Content

R. Nikolaiev
L. Rostomyan
A. Beckers
O. Khyzhnyak
M. Mykytyuk
Yu. Karatchentsev
V. Khaziev


Background. This article presents a review of the current literature on the role of the genetic component in the etiology and pathogenesis of hormone-active pituitary adenomas secreting growth hormone (GH) and clinically manifesting by acromegaly and/or gigantism (multiple endocrine neoplasia 1 (MEN-1), McCune-Albright syndrome, Carney complex, X-linked acrogigantism (X-LAG), familial isolated pituitary adenoma — FIPA). Materials and methods. To identify mutations in the AIP gene and to verify FIPA, 26 patients of the Ukrainian population (19 women and 7 men) were examined in whom acromegaly was diagnosed in adolescence or young age, and genetic analysis was performed. To determine the genetic determinism in the development of GH-secreting pituitary adenoma and differential diagnosis of FIPA and MEN-1 syndromes by sequencing method (MLPA — ligation-dependent probe amplification), the genes MLPA, P244-C1 were studied involving exons 1–6 MEN1 gene, (MLPA, P017-D1) AIP gene. Results. Among those examined, only two patients had AIP gene mutations. In one patient, genetic screening for MEN1 gene mutation was negative and no clinical symptoms suggestive of McCune-Albright syndrome were detected. A variant heterozygous missense c.714C>G (p.Cys238Trp) was found in the AIP gene. This AIP gene assay is compatible with a genetic predisposition to develop pituitary adenoma. The offspring of this patient has a 50% chance of inheriting this variant, acromegaly, hypersomatotropinemia, MEN-1 syndrome, familial isolated pituitary adenoma. Another patient was diagnosed with MEN syndrome type 1 (Wermer syndrome): insulinoma, parathyroid gland adenomas (2), primary hyperparathyroidism with a heterozygous c.134A>G variant (p.Glu45Gly) found in the MEN1 gene. The presence of the c.l34A>G (p.Glu45Gly) class variant 4 is likely to be pathogenic. The prevalence of this variant in the general population is unknown, so it is very rare. Conclusions. The genetic analysis is appropriate in pediatric and young patients or those with GH-secreting macro/giant pituitary adenoma diagnosed at a young age (under 35), regardless of family history. In patients with a history of a disease, genetic analysis is recommended in any case to identify FIPA and to predict the further course of the disease and the effectiveness of treatment with somatostatin analogues.

Article Details

How to Cite
Nikolaiev, R., L. Rostomyan, A. Beckers, O. Khyzhnyak, M. Mykytyuk, Y. Karatchentsev, and V. Khaziev. “Modern Views on the Genetic Determinism of GH-Secreting Pituitary Adenomas (literature Review and Own Data)”. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine), vol. 17, no. 1, Apr. 2021, pp. 11-19, doi:10.22141/2224-0721.17.1.2021.226425.
Original Researches


Lavrentaki A, Paluzzi A, Wass JA, Karavitaki N. Epidemiology of acromegaly: review of population studies. Pituitary. 2017 Feb;20(1):4-9. doi:10.1007/s11102-016-0754-x.

Maione L, Chanson P. National acromegaly registries. Best Pract Res Clin Endocrinol Metab. 2019 Apr;33(2):101264. doi:10.1016/j.beem.2019.02.001.

Khyzhnyak O, Mykytyuk M, Guk M, Nikolaiev R, Gogitidze T. Clinical and hormonal features of acromegaly in patients from a Ukrainian neuroendocrinology centre. Probl Endocr Pathol. 2019;(68):119-130. doi:10.21856/j-PEP.2019.2.17.

Gao M, Zhu B, Xu Z, et al. Association between acromegaly and a single nucleotide polymorphism (rs2854744) in the IGFBP3 gene. BMC Med Genet. 2018 Oct 5;19(1):182. doi:10.1186/s12881-018-0698-2.

Sapochnik M, Nieto LE, Fuertes M, Arzt E. Molecular Mechanisms Underlying Pituitary Pathogenesis. Biochem Genet. 2016 Apr;54(2):107-119. doi:10.1007/s10528-015-9709-6.

Rostomyan L, Daly AF, Petrossians P, et al. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer. 2015 Oct;22(5):745-757. doi:10.1530/ERC-15-0320.

Nikolaiev R, Standel S, Khyzhnyak O, Mikityuk M, Manska K. Features of hereditary aptitude to the development of the pituitary adenoma according to the data of the Ukrainian neuro-endocrinological center. Probl Endocr Pathol. 2020;(73):71-80. doi:10.21856/j-PEP.2020.3.09. (in Ukrainian).

Iacovazzo D, Hernández-Ramírez LC, Korbonits M. Sporadic pituitary adenomas: the role of germline mutations and recommendations for genetic screening. Expert Rev Endocrinol Metab. 2017 Mar;12(2):143-153. doi:10.1080/17446651.2017.1306439. 

Hernandez-Ramirez LC, Korbonits M. Familiar pituitary adenomas. In: Laws ER, Ezzat S, Asa SL, Rio ML, Michel L, Knutzen R, editors. Pituitary Disorders: Diagnosis and Management. Chichester, UK: Wiley-Blackwell; 2013. 87-110 pp.

Vergès B, Boureille F, Goudet P, 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):457-465. doi:10.1210/jcem.87.2.8145.

Horvath A, Stratakis CA. Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune-Albright syndrome, familial acromegaly and genetic defects in sporadic tumors. Rev Endocr Metab Disord. 2008 Mar;9(1):1-11. doi:10.1007/s11154-007-9066-9.

Hernández-Ramírez LC, Gabrovska P, 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. doi:10.1210/jc.2015-1869.

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. doi:10.1016/j.ecl.2014.10.002.

Chahal HS, Chapple JP, Frohman LA, Grossman AB, Korbonits M. Clinical, genetic and molecular characterization of patients with familial isolated pituitary adenomas (FIPA). Trends Endocrinol Metab. 2010 Jul;21(7):419-427. doi:10.1016/j.tem.2010.02.007.

Srirangam Nadhamuni V, Korbonits M. Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms. Endocr Rev. 2020 Dec 1;41(6):821–846. doi:10.1210/endrev/bnaa006.

Beckers A, Aaltonen LA, Daly AF, Karhu A. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev. 2013 Apr;34(2):239-277. doi:10.1210/er.2012-1013.

Gadelha MR, Trivellin G, Hernández Ramírez LC, Korbonits M. Genetics of pituitary adenomas. Front Horm Res. 2013;41:111-140. doi:10.1159/000345673.

Mnif Feki M, Mnif F, Kamoun M, et al. Ectopic secretion of GHRH by a pancreatic neuroendocrine tumor associated with an empty sella. Ann Endocrinol (Paris). 2011 Dec;72(6):522-525. doi:10.1016/j.ando.2011.06.002.

Biswal S, Srinivasan B, Dutta P, et al. Acromegaly caused by ectopic growth hormone: a rare manifestation of a bronchial carcinoid. Ann Thorac Surg. 2008 Jan;85(1):330-332. doi:10.1016/j.athoracsur.2007.06.072.

Mankin HJ, Jupiter J, Trahan CA. Hand and foot abnormalities associated with genetic diseases. Hand (N Y). 2011 Mar;6(1):18-26. doi:10.1007/s11552-010-9302-8.

Vandeva S, Tichomirowa MA, Zacharieva S, Daly AF, Beckers A. Genetic factors in the development of pituitary adenomas. Endocr Dev. 2010;17:121-133. doi:10.1159/000262534.

Borson-Chazot F, Garby L, Raverot G, et al. Acromegaly induced by ectopic secretion of GHRH: a review 30 years after GHRH discovery. Ann Endocrinol (Paris). 2012 Dec;73(6):497-502. doi:10.1016/j.ando.2012.09.004.

Boikos SA, Stratakis CA. Carney complex: pathology and molecular genetics. Neuroendocrinology. 2006;83(3-4):189-199. doi:10.1159/000095527.

Raverot G, Arnous W, Calender A, et al. Familial pituitary adenomas with a heterogeneous functional pattern: clinical and genetic features. J Endocrinol Invest. 2007 Oct;30(9):787-790. doi:10.1007/BF03350819.

You C, Qiao F, Jiang S, Xiao A. Growth hormone secreting pituitary adenoma associated with Rathke's cleft cyst. Neurol India. 2012 May-Jun;60(3):310-311. doi:10.4103/0028-3886.98521.

Phillips JD, Yeldandi A, Blum M, de Hoyos A. Bronchial carcinoid secreting insulin-like growth factor-1 with acromegalic features. Ann Thorac Surg. 2009 Oct;88(4):1350-1352. doi:10.1016/j.athoracsur.2009.02.042.

Caimari F, Korbonits M. Novel Genetic Causes of Pituitary Adenomas. Clin Cancer Res. 2016 Oct 15;22(20):5030-5042. doi:10.1158/1078-0432.CCR-16-0452.

Pepe S, Korbonits M, Iacovazzo D. Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects. J Endocrinol. 2019 Feb 1;240(2):R21-R45. doi:10.1530/JOE-18-0446.

Tatsi C, Stratakis CA. The Genetics of Pituitary Adenomas. J Clin Med. 2019 Dec 21;9(1):30. doi:10.3390/jcm9010030.

Ozcan-Kara P, Mahmoudian B, Erbas B, Erbas T. McCune-Albright syndrome associated with acromegaly and bipolar affective disorder. Eur J Intern Med. 2007 Dec;18(8):600-602. doi:10.1016/j.ejim.2007.02.030.

Sung SH, Yoon HD, Shon HS, et al. A case of McCune-Albright syndrome with associated multiple endocrinopathies. Korean J Intern Med. 2007 Mar;22(1):45-50. doi:10.3904/kjim.2007.22.1.45.

Collins MT, Singer FR, Eugster E. McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis. 2012 May 24;7(Suppl 1):S4. doi:10.1186/1750-1172-7-S1-S4.

Salenave S, Boyce AM, Collins MT, Chanson P. Acromegaly and McCune-Albright syndrome. J Clin Endocrinol Metab. 2014 Jun;99(6):1955-1969. doi:10.1210/jc.2013-3826.

Zatelli MC, Tagliati F, Di Ruvo M, et al. Deletion of exons 1-3 of the MEN1 gene in a large Italian family causes the loss of menin expression. Fam Cancer. 2014 Jun;13(2):273-280. doi:10.1007/s10689-014-9702-y.

Kamilaris CDC, Stratakis CA. Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis. Front Endocrinol (Lausanne). 2019 Jun 11;10:339. doi:10.3389/fendo.2019.00339.

Lemos MC, Thakker RV. 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. doi:10.1002/humu.20605.

Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep;97(9):2990-3011. doi:10.1210/jc.2012-1230.

Espiard S, Bertherat J. Carney complex. Front Horm Res. 2013;41:50-62. doi:10.1159/000345669.

Cazabat L, Ragazzon B, Groussin L, Bertherat J. PRKAR1A mutations in primary pigmented nodular adrenocortical disease. Pituitary. 2006;9(3):211-219. doi:10.1007/s11102-006-0266-1.

Bosco Schamun MB, Correa R, Graffigna P, de Miguel V, Fainstein Day P. Carney complex review: Genetic features. Endocrinol Diabetes Nutr. 2018 Jan;65(1):52-59. doi:10.1016/j.endinu.2017.09.006.

Matyakhina L, Pack S, Kirschner LS, et al. Chromosome 2 (2p16) abnormalities in Carney complex tumours. J Med Genet. 2003 Apr;40(4):268-277. doi:10.1136/jmg.40.4.268.

Forlino A, Vetro A, Garavelli L, et al. PRKACB and Carney complex. N Engl J Med. 2014 Mar 13;370(11):1065-1067. doi:10.1056/NEJMc1309730.

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):4041-4046. doi:10.1210/jcem.86.9.7903.

Shetty Roy AN, Radin M, Sarabi D, Shaoulian E. Familial recurrent atrial myxoma: Carney's complex. Clin Cardiol. 2011 Feb;34(2):83-86. doi:10.1002/clc.20845.

Kamilaris CDC, Faucz FR, Voutetakis A, Stratakis CA. Carney Complex. Exp Clin Endocrinol Diabetes. 2019 Feb;127(2-03):156-164. doi:10.1055/a-0753-4943.

Malicka J, Świrska J, Nowakowski A. Familial acromegaly – case study of two sisters with acromegaly. Endokrynol Pol. 2011;62(6):554-557.

Beckers A, Daly AF. The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol. 2007 Oct;157(4):371-382. doi:10.1530/EJE-07-0348.

Aaltonen LA. Aryl hydrocarbon receptor-interacting protein and acromegaly. Horm Res. 2007;68(Suppl 5):127-131. doi:10.1159/000110607.

Rostomyan L, Beckers A. Screening for genetic causes of growth hormone hypersecretion. Growth Horm IGF Res. 2016 Oct-Dec;30-31:52-57. doi:10.1016/j.ghir.2016.10.004.

Melmed S, Bronstein MD, Chanson P, et al. A Consensus Statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018 Sep;14(9):552-561. doi:10.1038/s41574-018-0058-5.

Leontiou CA, Gueorguiev M, van der Spuy J, et al. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metab. 2008 Jun;93(6):2390-2401. doi:10.1210/jc.2007-2611.

Igreja S, Chahal HS, King P, et al. Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum Mutat. 2010 Aug;31(8):950-960. doi:10.1002/humu.21292.

Hernández-Ramírez LC, Martucci F, Morgan RM, et al. Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations. J Clin Endocrinol Metab. 2016 Aug;101(8):3144-3154. doi:10.1210/jc.2016-1307.

Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424. doi:10.1038/gim.2015.30.

Starker LF, Akerström T, Long WD, et al. Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism. Horm Cancer. 2012 Apr;3(1-2):44-51. doi:10.1007/s12672-011-0100-8.

Pardi E, Borsari S, Saponaro F, et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 2017 Oct 16;12(10):e0186485. doi:10.1371/journal.pone.0186485.

Kihara M, Miyauchi A, Ito Y, et al. MEN1 gene analysis in patients with primary hyperparathyroidism: 10-year experience of a single institution for thyroid and parathyroid care in Japan. Endocr J. 2009;56(5):649-656. doi:10.1507/endocrj.k08e-265.

Sato M, Kihara M, Nishitani A, et al. Large and asymptomatic pancreatic islet cell tumor in a patient with multiple endocrine neoplasia type 1. Endocrine. 2000 Dec;13(3):263-266. doi:10.1385/ENDO:13:3:263.

Miyauchi A, Sato M, Matsubara S, et al. A family of MEN1 with a novel germline missense mutation and benign polymorphisms. Endocr J. 1998 Dec;45(6):753-759. doi:10.1507/endocrj.45.753.

Vierimaa O, Georgitsi M, Lehtonen R, et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science. 2006 May 26;312(5777):1228-1230. doi:10.1126/science.1126100.

Iwata T, Yamada S, Mizusawa N, Golam HM, Sano T, Yoshimoto K. The aryl hydrocarbon receptor-interacting protein gene is rarely mutated in sporadic GH-secreting adenomas. Clin Endocrinol (Oxf). 2007 Apr;66(4):499-502. doi:10.1111/j.1365-2265.2007.02758.x.

Korbonits M, Storr H, Kumar AV. Familial pituitary adenomas – who should be tested for AIP mutations? Clin Endocrinol (Oxf). 2012 Sep;77(3):351-356. doi:10.1111/j.1365-2265.2012.04445.x.

Personnier C, Cazabat L, Bertherat J, et al. Clinical features and treatment of pediatric somatotropinoma: case study of an aggressive tumor due to a new AIP mutation and extensive literature review. Horm Res Paediatr. 2011;75(6):392-402. doi:10.1159/000327831.

Joshi K, Daly AF, Beckers A, Zacharin M. Resistant Paediatric Somatotropinomas due to AIP Mutations: Role of Pegvisomant. Horm Res Paediatr. 2018;90(3):196-202. doi:10.1159/000488856.