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The causes and consequences of pituitary gigantism

Nature Reviews Endocrinology volume 14, pages 705–720 (2018)Cite this article

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Abstract

In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.

Key points

  • Nearly 50% of patients with pituitary gigantism have a known underlying genetic cause; therefore, these patients should be strongly considered for genetic counselling and screening.

  • Once growth hormone (GH) hypersecretion has been established, efforts should be made to avoid delays in instigating treatment to control levels of GH and insulin-like growth factor 1.

  • A shorter time between diagnosis and the commencement of treatment is associated with a decreased final height in pituitary gigantism.

  • Pituitary gigantism is a disease that predominantly affects males, but males also have a longer delay in time to diagnosis than females, leading to a low proportion of male patients who have disease control by 18 years of age.

  • Somatotropinomas in pituitary gigantism are usually large (macroadenomas) and might be difficult to cure with surgery or medical therapy alone; therefore, multimodal approaches are common in pituitary gigantism.

  • The effect of large tumour size and multiple surgeries and radiotherapy is that patients with pituitary gigantism often have hypopituitarism at long-term follow-up.

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Fig. 1: An historical patient with pituitary gigantism.
Fig. 2: Signs and symptoms in pituitary gigantism at diagnosis.
Fig. 3: Evolution of the severity of signs and symptoms of pituitary gigantism before and after treatment.
Fig. 4: Schematic for performing genetic investigations in patients with pituitary gigantism.

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References

  1. Jelenkovic, A. et al. Genetic and environmental influences on height from infancy to early adulthood: an individual-based pooled analysis of 45 twin cohorts. Sci. Rep. 6, 28496 (2016).

    PubMed  PubMed Central  Google Scholar 

  2. Jelenkovic, A. et al. Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994. eLife 5, e20320 (2016).

    PubMed  PubMed Central  Google Scholar 

  3. Berndt, S. I. et al. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nat. Genet. 45, 501–512 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Macé, A. et al. CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits. Nat. Commun. 8, 744 (2017). This complex analysis shows the importance of CNV as well as mutation on human height.

    PubMed  PubMed Central  Google Scholar 

  5. Zong, X.-N., Li, H., Wu, H.-H. & Zhang, Y.-Q. Socioeconomic development and secular trend in height in China. Econ. Hum. Biol. 19, 258–264 (2015).

    PubMed  Google Scholar 

  6. Fudvoye, J. & Parent, A.-S. Secular trends in growth. Ann. Endocrinol. (Paris). 78, 88–91 (2017).

    Google Scholar 

  7. Hermanussen, M. et al. Growth variation, final height and secular trend. Proceedings of the 17th Aschauer Soiree, 7th November 2009. HOMO 61, 277–284 (2010).

    CAS  PubMed  Google Scholar 

  8. Judge, T. A. & Cable, D. M. The effect of physical height on workplace success and income: preliminary test of a theoretical model. J. Appl. Physchol. 89, 428–441 (2004).

    Google Scholar 

  9. Deaton, A. S., Hall, W. & School, W. W. Life at the top: the benefits of height. Econ. Hum. Biol. 7, 133–136 (2009).

    PubMed  PubMed Central  Google Scholar 

  10. Lee, J. M. & Howell, J. D. Tall girls: the social shaping of a medical therapy. Arch. Pediatr. Adolesc. Med. 160, 1035–1039 (2006).

    PubMed  Google Scholar 

  11. Rayner, J.-A., Pyett, P. & Astbury, J. The medicalisation of ‘tall’ girls: a discourse analysis of medical literature on the use of synthetic oestrogen to reduce female height. Soc. Sci. Med. 71, 1076–1083 (2010).

    PubMed  Google Scholar 

  12. Hannema, S. E. & Sävendahl, L. Clinical practice the evaluation and management of tall stature. Horm. Res. Paediatr. 85, 347–352 (2016).

    CAS  PubMed  Google Scholar 

  13. Davies, J. H. & Cheetham, T. Investigation and management of tall stature. Arch. Dis. Child 99, 772–777 (2014). This article provides a concise and practical overview of the clinical assessment and management of tall stature.

    PubMed  Google Scholar 

  14. Stalman, S. E., Pons, A., Wit, J. M., Kamp, G. A. & Plötz, F. B. Diagnostic work-up and follow-up in children with tall stature: a simplified algorithm for clinical practice. J. Clin. Res. Pediatr. Endocrinol. 7, 260–267 (2015).

    PubMed  PubMed Central  Google Scholar 

  15. Coutant, R., Donzeau, A., Decrequy, A., Louvigné, M. & Bouhours-Nouet, N. How to investigate a child with excessive growth? Ann. Endocrinol. (Paris). 78, 98–103 (2017).

    Google Scholar 

  16. Baron, J. et al. Short and tall stature: a new paradigm emerges. Nat. Rev. Endocrinol. 11, 735–746 (2015). This paper is an excellent overview of the past findings and future directions of human height research.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jee, Y. H., Andrade, A. C., Baron, J. & Nilsson, O. Genetics of short stature. Endocrinol. Metab. Clin. North Am. 46, 259–281 (2017).

    PubMed  PubMed Central  Google Scholar 

  18. Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Committee on Genetics. Health supervision children with Marfan syndrome. Pediatrics 132, e1059–e1072 (2013).

    Google Scholar 

  20. Verge, C. F. & Mowat, D. Overgrowth. Arch. Dis. Child. 95, 458–463 (2010).

    PubMed  Google Scholar 

  21. Barstow, C. & Rerucha, C. Evaluation of short and tall stature in children. Am. Fam. Physician 92, 43–50 (2015).

    PubMed  Google Scholar 

  22. Meazza, C., Gertosio, C., Giacchero, R., Pagani, S. & Bozzola, M. Tall stature: a difficult diagnosis? Ital. J. Pediatr. 43, 66 (2017).

    PubMed  PubMed Central  Google Scholar 

  23. Albuquerque, E. V. A., Scalco, R. C. & Jorge, A. A. L. MANAGEMENT OF ENDOCRINE DISEASE: diagnostic and therapeutic approach of tall stature. Eur. J. Endocrinol. 176, R339–R353 (2017).

    CAS  PubMed  Google Scholar 

  24. Stratakis, C. A. A giant? Think of genetics: growth hormone-producing adenomas in the young are almost always the result of genetic defects. Endocrine 50, 272–275 (2015).

    CAS  PubMed  Google Scholar 

  25. Rostomyan, L. et al. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr. Relat. Cancer 22, 745–757 (2015). This article presents the first international study using standardized data collection to assess the characteristics of pituitary gigantism.

    CAS  PubMed  Google Scholar 

  26. Rostomyan, L., Daly, A. F. & Beckers, A. Pituitary gigantism: causes and clinical characteristics. Ann. Endocrinol. (Paris). 76, 643–649 (2015).

    Google Scholar 

  27. Garnier, E. Enanos y Gigantes (Daniel Cortezo, Barcelona, 1886).

  28. de Herder, W. W. [Giantism. A historical and medical view]. Ned Tijdschr. Geneeskd 148, 2585–2590 (2004).

    PubMed  Google Scholar 

  29. de Herder, W. W. Acromegaly and gigantism in the medical literature. Case descriptions in the era before and the early years after the initial publication of Pierre Marie (1886). Pituitary 12, 236–244 (2009). This paper provides expert historical background of the medical study of gigantism and acromegaly.

    PubMed  Google Scholar 

  30. Fritsche, E. & Klebs, E. Ein Beitrag zur Pathologie des Riesenwuchses. Klinische und Pathologisch -Anatomische Untersuchungen (F. C. W. Vogel, 1884).

  31. Marie, P. Sur deux cas d’acromegalie. Hypertrophe singuliere no congénitale des extréméties supérieures, inférieures et cephalique [French]. Révue Méd. Française 6, 297–333 (1886).

    Google Scholar 

  32. Marie, P. & de Souza Leite, J. D. Essays on Acromegaly (The New Sydenham Society, 1891).

  33. de Herder, W. W. A postcard of a giant and his physician (collection de Herder, W. W.). J. Endocrinol. Invest. 28, 392 (2005).

    PubMed  Google Scholar 

  34. Dana, C. L. Giants and gigantism. Scribner’ Mag. 17, 179–185 (1895).

    Google Scholar 

  35. Hinsdale, G. Acromegaly: an essay to which was awarded the Boylston Prize of Harvard University for the year 1898 (William W. Warren, 1898).

  36. Launois, P. É. & Roy, P. Études Biologiques sur les Géants (Masson et Cie, 1904).

  37. Dufrane, A., Launois, P. E. & Roy, P. Les Relations du Gigantisme et L’acromegalie Expliquees par L’autopsie du Géant Constantin (Masson, Paris, 1903).

    Google Scholar 

  38. Launois, P. É. in Comptes Rendus de l’Association des Anatomistes, Cinquième Session (ed. Nicolas, A.) 51–54 (Institute Anatomique, 1903).

  39. Cushing, H. The Pituitary Body and Its Disorders (J. B. Lippincott Company, 1912).

  40. Beclère, A. Le traitement medical des tumeurs hypophysaires, du gigantisme et de I’acromégalie par la radiothérapie [French]. Arch. d’Electricité Méd. Exp. Clin. 17, 163–180 (1909).

    Google Scholar 

  41. Melmed, S. et al. A consensus on the diagnosis and treatment of acromegaly complications. Pituitary 16, 294–302 (2013).

    CAS  PubMed  Google Scholar 

  42. Katznelson, L. et al. Acromegaly: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99, 3933–3951 (2014).

    CAS  PubMed  Google Scholar 

  43. Petrossians, P. et al. Acromegaly at diagnosis in 3173 patients from the Liège Acromegaly Survey (LAS) database. Endocr. Relat. Cancer 24, 505–518 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Beckers, A. et al. X-Linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocr. Relat. Cancer 22, 353–367 (2015). This article presents a detailed assessment of the unique clinical features of X-LAG syndrome.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Trivellin, G. et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N. Engl. J. Med. 371, 2363–2374 (2014). This publication presents the discovery and description of X-LAG syndrome.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Beckers, A., Aaltonen, L. A., Daly, A. F. & 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. 34, (239–277 (2013).

    Google Scholar 

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

    Google Scholar 

  48. Martucci, F., Trivellin, G. & Korbonits, M. Familial isolated pituitary adenomas: an emerging clinical entity. J. Endocrinol. Invest. 35, 1003–1014 (2012).

    CAS  PubMed  Google Scholar 

  49. Hannah-Shmouni, F., Trivellin, G. & Stratakis, C. A. Genetics of gigantism and acromegaly. Growth Horm. IGF Res. 30–31, 37–41 (2016).

    PubMed  PubMed Central  Google Scholar 

  50. Daly, A. F. et al. Clinical characterization of familial isolated pituitary adenomas. J. Clin. Endocrinol. Metab. 91, 3316–3323 (2006). This article presents the initial clinical description and definition of FIPAs, the most frequently encountered familial pituitary adenoma presentation.

    CAS  PubMed  Google Scholar 

  51. Daly, A. F. 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. 95, E373–E383 (2010). This large cohort study establishes the significant differences in disease characteristics and therapeutic responses between acromegaly and gigantism due to AIP mutations versus non-mutated cases.

    PubMed  Google Scholar 

  52. Hernández-Ramírez, L. C. et al. Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. J. Clin. Endocrinol. Metab. 100, E1242–E1254 (2015). This paper provides an in-depth analysis of the role of AIP mutations in sporadic and familial pituitary adenoma.

    PubMed  PubMed Central  Google Scholar 

  53. Trivellin, G. & Korbonits, M. AIP and its interacting partners. J. Endocrinol. 210, 137–155 (2011).

    CAS  PubMed  Google Scholar 

  54. Chahal, H. S. et al. Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. J. Clin. Endocrinol. Metab. 97, 1–10 (2012).

    Google Scholar 

  55. Bolger, G. B. et al. Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2. J. Biol. Chem. 278, 33351–33363 (2003).

    CAS  PubMed  Google Scholar 

  56. Ritvonen, E. et al. Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas. Eur. J. Endocrinol. 176, 243–252 (2017).

    CAS  PubMed  Google Scholar 

  57. Tuominen, I. et al. AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling. Oncogene 34, 1174–1184 (2015).

    CAS  PubMed  Google Scholar 

  58. de Oliveira, S. K. & Smolenski, A. Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling. Biochem. Pharmacol. 77, 723–733 (2009).

    PubMed  Google Scholar 

  59. Linnert, M. et al. The FKBP-type domain of the human aryl hydrocarbon receptor-interacting protein reveals an unusual Hsp90 interaction. Biochemistry 52, 2097–2107 (2013).

    CAS  PubMed  Google Scholar 

  60. Formosa, R., Xuereb-Anastasi, A. & Vassallo, J. AIP regulates cAMP signalling and growth hormone secretion in GH3 cells. Endocr. Relat. Cancer 20, 495–505 (2013).

    CAS  PubMed  Google Scholar 

  61. Lecoq, A.-L. et al. AIP mutations impair AhR signaling in pituitary adenoma patients fibroblasts and in GH3 cells. Endocr. Relat. Cancer 23, 433–443 (2016).

    CAS  PubMed  Google Scholar 

  62. Hernández-Ramírez, L. C. et al. Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland. Oncotarget 9, 9177–9198 (2018).

    PubMed  PubMed Central  Google Scholar 

  63. Hernández-Ramírez, L. C. 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. 101, 3144–3154 (2016).

    PubMed  PubMed Central  Google Scholar 

  64. Morgan, R. M. L. et al. Structure of the TPR domain of AIP: lack of client protein interaction with the C-terminal α-7 helix of the TPR domain of AIP is sufficient for pituitary adenoma predisposition. PLOS ONE 7, e53339 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Formosa, R. & Vassallo, J. Aryl hydrocarbon receptor–interacting protein (AIP) N-terminus gene mutations identified in pituitary adenoma patients alter protein stability and function. Horm. Cancer 8, (174–184 (2017).

    Google Scholar 

  66. Cannavo, S. et al. Increased prevalence of acromegaly in a highly polluted area. Eur. J. Endocrinol. 163, 509–513 (2010).

    CAS  PubMed  Google Scholar 

  67. Cannavo, S. et al. Acromegaly is more severe in patients with AHR or AIP gene variants living in highly polluted areas. J. Clin. Endocrinol. Metab. 101, (1872–1879 (2016).

    Google Scholar 

  68. Cannavo, S., Trimarchi, F. & Ferraù, F. Acromegaly, genetic variants of the aryl hydrocarbon receptor pathway and environmental burden. Mol. Cell. Endocrinol. 457, 81–88 (2017).

    CAS  PubMed  Google Scholar 

  69. Lin, B. C. et al. Deletion of the aryl hydrocarbon receptor-associated protein 9 leads to cardiac malformation and embryonic lethality. J. Biol. Chem. 282, 35924–35932 (2007).

    CAS  PubMed  Google Scholar 

  70. Raitila, A. et al. Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression. Am. J. Pathol. 177, (1969–1976 (2010).

    Google Scholar 

  71. Lecoq, A.-L. et al. Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice. J. Endocrinol. 231, 59–69 (2016).

    CAS  PubMed  Google Scholar 

  72. Gillam, M. P. et al. Somatotroph-specific aip-deficient mice display pretumorigenic alterations in cell-cycle signaling. J. Endocr. Soc. 1, 78–95 (2017).

    PubMed  PubMed Central  Google Scholar 

  73. Villa, C. et al. Hyperplasia-adenoma sequence in pituitary tumorigenesis related to aryl hydrocarbon receptor interacting protein gene mutation. Endocr. Relat. Cancer 18, 347–356 (2011).

    CAS  PubMed  Google Scholar 

  74. Vierimaa, O. et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312, 1228–1230 (2006). This study describes the discovery of AIP mutations as an inherited cause of pituitary adenomas.

    CAS  PubMed  Google Scholar 

  75. Nagata, Y. et al. Growth hormone-producing pituitary adenomas in childhood and young adulthood: clinical features and outcomes. Pituitary 21, 1–9 (2018).

    CAS  PubMed  Google Scholar 

  76. Naves, L. A. et al. Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene. Eur. J. Endocrinol. 157, 383–391 (2007).

    CAS  PubMed  Google Scholar 

  77. Georgitsi, M. et al. Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Proc. Natl Acad. Sci. USA 104, 4101–4105 (2007).

    CAS  PubMed  Google Scholar 

  78. Tichomirowa, M. A. et al. High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. Eur. J. Endocrinol. 165, 509–515 (2011).

    CAS  PubMed  Google Scholar 

  79. Daly, A. F. et al. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J. Clin. Endocrinol. Metab. 92, 1891–1896 (2007).

    CAS  PubMed  Google Scholar 

  80. Cuny, T. et al. Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don’t forget MEN1 genetic analysis. Eur. J. Endocrinol. 168, 533–541 (2013).

    CAS  PubMed  Google Scholar 

  81. Stratakis, C. A. et al. The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clin. Genet. 78, 457–463 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Chahal, H. S. et al. AIP mutation in pituitary adenomas in the 18th century and today. N. Engl. J. Med. 364, 43–50 (2011). This historical and genetic study links present-day patients with acromegaly and gigantism to an AIP founder mutation.

    CAS  PubMed  Google Scholar 

  83. Williams, F. et al. Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation. J. Clin. Endocrinol. Metab. 99, 1122–1131 (2014).

    Google Scholar 

  84. Igreja, S. et al. Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum. Mutat. 31, 950–960 (2010).

    Google Scholar 

  85. Leontiou, C. A. et al. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J. Clin. Endocrinol. Metab. 93, 2390–2401 (2008).

    CAS  PubMed  Google Scholar 

  86. Salvatori, R., Daly, A. F., Quinones-Hinojosa, A., Thiry, A. & Beckers, A. A clinically novel AIP mutation in a patient with a very large, apparently sporadic somatotrope adenoma. Endocrinol. Diabetes Metab. Case Rep. 2014, 140048 (2014).

    PubMed  PubMed Central  Google Scholar 

  87. Jaffrain-Rea, M.-L. et al. Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications. Endocr. Relat. Cancer 16, 1029–1043 (2009).

    CAS  PubMed  Google Scholar 

  88. Jaffrain-Rea, M.-L. et al. Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. Endocr. Relat. Cancer 20, 753–766 (2013).

    CAS  PubMed  Google Scholar 

  89. Kasuki, L. et al. AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SSTR2 expression. Endocr. Relat. Cancer 19, L25–L29 (2012).

    CAS  PubMed  Google Scholar 

  90. Kasuki Jomori de Pinho, L. et al. Low aryl hydrocarbon receptor-interacting protein expression is a better marker of invasiveness in somatotropinomas than Ki-67 and p53. Neuroendocrinology 94, 39–48 (2011).

    PubMed  Google Scholar 

  91. Imran, S. A. et al. Unusual AIP mutation and phenocopy in the family of a young patient with acromegalic gigantism. Endocrinol. Diabetes Metab. Case Rep. https://doi.org/10.1530/EDM-17-0092 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Salvatori, R. et al. In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism. Eur. J. Endocrinol. 177, 257–266 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Radian, S. et al. Increased population risk of AIP-related acromegaly and gigantism in Ireland. Hum. Mutat. 38, 78–85 (2017).

    CAS  PubMed  Google Scholar 

  94. de Herder, W. W. et al. Acromegalic gigantism, physicians and body snatching. Past or present? Pituitary 15, 312–318 (2012).

    PubMed  PubMed Central  Google Scholar 

  95. Vasilev, V. et al. MANAGEMENT OF ENDOCRINE DISEASE: pituitary ‘incidentaloma’: neuroradiological assessment and differential diagnosis. Eur. J. Endocrinol. 175, R171–R184 (2016).

    CAS  PubMed  Google Scholar 

  96. Ezzat, S. et al. The prevalence of pituitary adenomas: a systematic review. Cancer 101, 613–619 (2004).

    PubMed  Google Scholar 

  97. Rodd, C. et al. Somatic GPR101 duplication causing X-linked acrogigantism (XLAG) - diagnosis and management. J. Clin. Endocrinol. Metab. 101, 1927–1930 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Naves, L. A. et al. Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome. Endocrine 51, 236–244 (2016).

    CAS  PubMed  Google Scholar 

  99. Daly, A. F. et al. Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. Endocr. Relat. Cancer 23, 221–233 (2016). This study describes how X-LAG syndrome can be caused by mosaicism for chromosome Xq26.3 duplications and can be detected in the screening of patient cohorts using digital PCR.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Daly, A. F. et al. GHRH excess and blockade in X-LAG syndrome. Endocr. Relat. Cancer 23, 161–170 (2016).

    CAS  PubMed  Google Scholar 

  101. Trivellin, G., Hernández-Ramírez, L. C., Swan, J. & Stratakis, C. A. An orphan G-protein-coupled receptor causes human gigantism and/or acromegaly: molecular biology and clinical correlations. Best Pract. Res. Clin. Endocrinol. Metab. 32, 125–140 (2018).

    CAS  PubMed  Google Scholar 

  102. Iacovazzo, D. et al. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathol. Commun. 4, 56 (2016).

    PubMed  PubMed Central  Google Scholar 

  103. Gordon, R. J. et al. Childhood acromegaly due to X-linked acrogigantism: long term follow-up. Pituitary 19, 560–564 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Beckers, A. et al. Paleogenetic study of ancient DNA suggestive of X-linked acrogigantism. Endocr. Relat. Cancer 24, L17–L20 (2017).

    PubMed  Google Scholar 

  105. Beckers, A., Rostomyan, L., Potorac, I., Beckers, P. & Daly, A. F. X-LAG: how did they grow so tall? Ann. Endocrinol. (Paris) 78, 131–136 (2017).

    Google Scholar 

  106. Trivellin, G. et al. Characterization of GPR101 transcript structure and expression patterns. J. Mol. Endocrinol. 57, 97–111 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Castinetti, F. et al. GPR101 mutations are not a frequent cause of congenital isolated growth hormone deficiency. Horm. Metab. Res. 48, 389–393 (2016).

    CAS  PubMed  Google Scholar 

  108. Kamenický, P., Bouligand, J. & Chanson, P. Gigantism, acromegaly, and GPR101 mutations. N. Engl. J. Med. 372, 1264–1265 (2015).

    PubMed  Google Scholar 

  109. Ferraù, F. et al. Analysis of GPR101 and AIP genes mutations in acromegaly: a multicentric study. Endocrine 54, 762–767 (2016).

    PubMed  Google Scholar 

  110. Daly, A. F., Trivellin, G. & Stratakis, C. A. Gigantism, acromegaly, and GPR101 mutations. N. Engl. J. Med. 372, 1265 (2015).

    PubMed  Google Scholar 

  111. Trivellin, G. et al. Screening for GPR101 defects in pediatric pituitary corticotropinomas. Endocr. Relat. Cancer 23, 357–365 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Brandi, M. L. et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J. Clin. Endocrinol. Metab. 86, 5658–5671 (2001).

    CAS  PubMed  Google Scholar 

  113. Thakker, R. V. et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 97, 2990–3011 (2012).

    CAS  PubMed  Google Scholar 

  114. Beckers, A., Betea, D., Valdes Socin, H. & Stevenaert, A. The treatment of sporadic versus MEN1-related pituitary adenomas. J. Intern. Med. 253, 599–605 (2003).

    CAS  PubMed  Google Scholar 

  115. Daly, A. F. & Beckers, A. in The Pituitary 4th edn (ed. Melmed, S.) 619–630 (Elsevier, 2017).

  116. Trouillas, J. et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am. J. Surg. Pathol. 32, 534–543 (2008).

    PubMed  Google Scholar 

  117. Sergeant, C. et al. Transdifferentiation of neuroendocrine cells: gangliocytoma associated with two pituitary adenomas of different lineage in MEN1. Am. J. Surg. Pathol. 41, 849–853 (2017).

    PubMed  Google Scholar 

  118. Magri, F. et al. Prevalence of double pituitary adenomas in a surgical series: clinical, histological and genetic features. J. Endocrinol. Invest. 33, 325–331 (2010).

    CAS  PubMed  Google Scholar 

  119. Vergès, B. et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J. Clin. Endocrinol. Metab. 87, 457–465 (2002).

    PubMed  Google Scholar 

  120. Syro, L. V. et al. Pituitary tumors in patients with MEN1 syndrome. Clinics (Sao Paulo) 67 (Suppl. 1), 43–48 (2012).

    Google Scholar 

  121. Stratakis, C. A. et al. Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1. J. Clin. Endocrinol. Metab. 85, 4776–4780 (2000).

    CAS  PubMed  Google Scholar 

  122. de Laat, J. M. et al. Long-term natural course of pituitary tumors in patients with MEN1: results from the Dutch MEN1 study group (DMSG). J. Clin. Endocrinol. Metab. 100, 3288–3296 (2015). This long-term cohort study of pituitary disease in MEN1 discusses the challenges of a modern screening programme.

    PubMed  Google Scholar 

  123. Huang, W. & Molitch, M. E. Management of nonfunctioning pituitary adenomas (NFAs): observation. Pituitary 21, 162–167 (2018).

    PubMed  Google Scholar 

  124. Albright, F., Butler, A. M., Hampton, A. O. & Smith, P. Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females. N. Engl. J. Med. 216, 727–746 (1937).

    Google Scholar 

  125. McCune, D. J. & Bruch, H. Osteodystrophia fibrosa. Am. J. Dis. Child. 54, 806 (1937).

    Google Scholar 

  126. Weinstein, L. S. et al. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N. Engl. J. Med. 325, 1688–1695 (1991). This study demonstrates that MAS is a Gα s -related disease.

    CAS  PubMed  Google Scholar 

  127. Schwindinger, W. F., Francomano, C. A. & Levine, M. A. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. Proc. Natl Acad. Sci. USA 89, 5152–5156 (1992).

    CAS  PubMed  Google Scholar 

  128. Dumitrescu, C. E. & Collins, M. T. McCune-Albright syndrome. Orphanet J. Rare Dis. 3, 12 (2008). This paper presents a comprehensive overview of the clinical presentation and pathology of MAS.

    PubMed  PubMed Central  Google Scholar 

  129. Zacharin, M. et al. Gastrointestinal polyps in McCune Albright syndrome. J. Med. Genet. 48, 458–461 (2011).

    PubMed  PubMed Central  Google Scholar 

  130. Wood, L. D. et al. Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas. Virchows Arch. 470, 391–400 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Vasilev, V. et al. McCune-Albright syndrome: a detailed pathological and genetic analysis of disease effects in an adult patient. J. Clin. Endocrinol. Metab. 99, E2029–E2038 (2014).

    CAS  PubMed  Google Scholar 

  132. Gaujoux, S. et al. Hepatobiliary and pancreatic neoplasms in patients with McCune-Albright syndrome. J. Clin. Endocrinol. Metab. 99, E97–E101 (2014).

    PubMed  Google Scholar 

  133. Salenave, S., Boyce, A. M., Collins, M. T. & Chanson, P. Acromegaly and McCune-Albright syndrome. J. Clin. Endocrinol. Metab. 99, 1955–1969 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Akintoye, S. O. et al. Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome. J. Clin. Endocrinol. Metab. 87, 5104–5112 (2002).

    CAS  PubMed  Google Scholar 

  135. Vortmeyer, A. O. et al. Somatic GNAS mutation causes widespread and diffuse pituitary disease in acromegalic patients with McCune-Albright syndrome. J. Clin. Endocrinol. Metab. 97, 2404–2413 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Schwindinger, W. F., Francomano, C. A., Levine, M. A. & McKusick, V. A. DNA light on the Tegernsee giant. Lancet 338, 1454–1455 (1991).

    CAS  PubMed  Google Scholar 

  137. Vogl, T. J., Nerlich, A., Dresel, S. H. & Bergman, C. CT of the “Tegernsee Giant”: juvenile gigantism and polyostotic fibrous dysplasia. J. Comput. Assist. Tomogr. 18, 319–322 (1994).

    CAS  PubMed  Google Scholar 

  138. Dötsch, J. et al. Gs alpha mutation at codon 201 in pituitary adenoma causing gigantism in a 6-year-old boy with McCune-Albright syndrome. J. Clin. Endocrinol. Metab. 81, 3839–3842 (1996).

    PubMed  Google Scholar 

  139. Queirolo, S. et al. Gigantism with pituitary macroadenoma: an unusual variant of McCune-Albright syndrome. J. Pediatr. Endocrinol. Metab. 22, 177–179 (2009).

    CAS  PubMed  Google Scholar 

  140. Nakagawa, H. et al. Gigantism associated with McCune-Albright’s syndrome. Horm. Metab. Res. 17, 522–527 (1985).

    CAS  PubMed  Google Scholar 

  141. Schoof, E. et al. Five-year follow-up of a 13-year-old boy with a pituitary adenoma causing gigantism-effect of octreotide therapy. Horm. Res. 61, 184–189 (2004).

    CAS  PubMed  Google Scholar 

  142. Lee, J. S. et al. Clinical guidelines for the management of craniofacial fibrous dysplasia. Orphanet J. Rare Dis. 7 (Suppl. 1), S2 (2012).

    PubMed  PubMed Central  Google Scholar 

  143. Boyce, A. M. et al. Optic neuropathy in McCune-Albright syndrome: effects of early diagnosis and treatment of growth hormone excess. J. Clin. Endocrinol. Metab. 98, E126–E134 (2013).

    CAS  PubMed  Google Scholar 

  144. Collins, M. T., Singer, F. R. & Eugster, E. McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J. Rare Dis. 7 (Suppl. 1), S4 (2012).

    PubMed  PubMed Central  Google Scholar 

  145. Belsuzarri, T. B. et al. McCune-Albright syndrome with craniofacial dysplasia: clinical review and surgical management. Surg. Neurol. Int. 7, 165 (2016).

    Google Scholar 

  146. Boyce, A. M. et al. Association of hearing loss and otologic outcomes with fibrous dysplasia. JAMA Otolaryngol. Neck Surg. 144, 102 (2018).

    Google Scholar 

  147. Akintoye, S. O. et al. Pegvisomant for the treatment of gsp-mediated growth hormone excess in patients with McCune-Albright syndrome. J. Clin. Endocrinol. Metab. 91, 2960–2966 (2006).

    CAS  PubMed  Google Scholar 

  148. Galland, F. et al. McCune-Albright syndrome and acromegaly: effects of hypothalamopituitary radiotherapy and/or pegvisomant in somatostatin analog-resistant patients. J. Clin. Endocrinol. Metab. 91, 4957–4961 (2006).

    CAS  PubMed  Google Scholar 

  149. Kirschner, L. S. et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat. Genet. 26, 89–92 (2000). This study is about the genetic identification of PRKAR1A as the cause of Carney complex.

    CAS  PubMed  Google Scholar 

  150. Carney, J. A., Gordon, H., Carpenter, P. C., Shenoy, B. V. & Go, V. L. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 64, 270–283 (1985).

    CAS  PubMed  Google Scholar 

  151. Raff, S. B., Carney, J. A., Krugman, D., Doppman, J. L. & Stratakis, C. A. Prolactin secretion abnormalities in patients with the ‘syndrome of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas’ (Carney complex). J. Pediatr. Endocrinol. Metab. 13, 373–379 (2000).

    CAS  PubMed  Google Scholar 

  152. Stergiopoulos, S. G. & Stratakis, C. A. Human tumors associated with Carney complex and germline PRKAR1A mutations: a protein kinase A disease! FEBS Lett. 546, 59–64 (2003).

    CAS  PubMed  Google Scholar 

  153. Stergiopoulos, S. G., Abu-Asab, M. S., Tsokos, M. & Stratakis, C. A. Pituitary pathology in Carney complex patients. Pituitary 7, 73–82 (2004).

    PubMed  PubMed Central  Google Scholar 

  154. Boikos, S. A. & Stratakis, C. A. Pituitary pathology in patients with Carney Complex: growth-hormone producing hyperplasia or tumors and their association with other abnormalities. Pituitary 9, 203–209 (2006).

    CAS  PubMed  Google Scholar 

  155. Pack, S. D. et al. 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. 85, 3860–3865 (2000).

    CAS  PubMed  Google Scholar 

  156. Pellegata, N. S. et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc. Natl Acad. Sci. USA 103, 15558–15563 (2006).

    CAS  PubMed  Google Scholar 

  157. Belar, O., De La Hoz, C., Perez-Nanclares, G., Castano, L. & Gaztambide, S. Novel mutations in MEN1, CDKN1B and AIP genes in patients with multiple endocrine neoplasia type 1 syndrome in Spain. Clin. Endocrinol. 76, 719–724 (2011).

    Google Scholar 

  158. Occhi, G. et al. A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLOS Genet. 9, e1003350 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Molatore, S. et al. A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization. Hum. Mutat. 31, E1825–E1835 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Georgitsi, M. et al. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J. Clin. Endocrinol. Metab. 92, 3321–3325 (2007).

    CAS  PubMed  Google Scholar 

  161. Georgitsi, M. MEN-4 and other multiple endocrine neoplasias due to cyclin-dependent kinase inhibitors (p27(Kip1) and p18(INK4C)) mutations. Best Pract. Res. Clin. Endocrinol. Metab. 24, 425–437 (2010).

    CAS  PubMed  Google Scholar 

  162. Tichomirowa, M. A. et al. Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. Endocr. Relat. Cancer 19, 233–241 (2012).

    CAS  PubMed  Google Scholar 

  163. Sambugaro, S. et al. Early onset acromegaly associated with a novel deletion in CDKN1B 5'UTR region. Endocrine 49, 58–64 (2015).

    CAS  PubMed  Google Scholar 

  164. Kiyokawa, H. et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 85, 721–732 (1996).

    CAS  PubMed  Google Scholar 

  165. Fero, M. L. et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85, 733–744 (1996).

    CAS  PubMed  Google Scholar 

  166. Nakayama, K. et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707–720 (1996).

    CAS  PubMed  Google Scholar 

  167. Xekouki, P. et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J. Clin. Endocrinol. Metab. 100, E710–E719 (2015). This paper provides an account of the emerging relationship of paraganglioma and phaeochromocytoma risk genes and pituitary tumours.

    PubMed  PubMed Central  Google Scholar 

  168. O’Toole, S. M., Dénes, J., Robledo, M., Stratakis, C. A. & Korbonits, M. 15 YEARS OF PARAGANGLIOMA: the association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr. Relat. Cancer 22, T105–T122 (2015).

    PubMed  Google Scholar 

  169. Dénes, J. et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J. Clin. Endocrinol. Metab. 100, E531–E541 (2015).

    PubMed  Google Scholar 

  170. Daly, A. F. et al. Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions. Endocr. Relat. Cancer 25, L37–L42 (2018).

    PubMed  Google Scholar 

  171. Tudorancea, A. et al. Von Hippel-Lindau disease and aggressive GH-PRL pituitary adenoma in a young boy. Ann. Endocrinol. (Paris). 73, 37–42 (2012).

    Google Scholar 

  172. Xekouki, P. 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. 97, E357–E366 (2011).

    PubMed  PubMed Central  Google Scholar 

  173. Cambiaso, P. et al. Growth hormone excess in children with neurofibromatosis type-1 and optic glioma. Am. J. Med. Genet. A 173A, 2353–2358 (2017).

    Google Scholar 

  174. Blanchard, G. et al. Systematic MRI in NF1 children under six years of age for the diagnosis of optic pathway gliomas. Study and outcome of a French cohort. Eur. J. Paediatr. Neurol. 20, 275–281 (2016).

    PubMed  Google Scholar 

  175. Cnossen, M. H. et al. Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1. Pediatrics 100, 667–670 (1997).

    CAS  PubMed  Google Scholar 

  176. Listernick, R., Ferner, R. E., Liu, G. T. & Gutmann, D. H. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann. Neurol. 61, 189–198 (2007).

    CAS  PubMed  Google Scholar 

  177. Sani, I. & Albanese, A. Endocrine long-term follow-up of children with neurofibromatosis type 1 and optic pathway glioma. Horm. Res. Paediatr. 87, 179–188 (2017).

    CAS  PubMed  Google Scholar 

  178. Segal, L., Darvish-Zargar, M., Dilenge, M.-E., Ortenberg, J. & Polomeno, R. C. Optic pathway gliomas in patients with neurofibromatosis type 1: follow-up of 44 patients. J. AAPOS 14, 155–158 (2010).

    PubMed  Google Scholar 

  179. Bruzzi, P., Sani, I. & Albanese, A. Reversible growth hormone excess in two girls with neurofibromatosis type 1 and optic pathway glioma. Horm. Res. Paediatr. 84, 414–422 (2015).

    CAS  PubMed  Google Scholar 

  180. Manski, T. J., Haworth, C. S., Duval-Arnould, B. J. & Rushing, E. J. Optic pathway glioma infiltrating into somatostatinergic pathways in a young boy with gigantism. Case report. J. Neurosurg. 81, 595–600 (1994).

    CAS  PubMed  Google Scholar 

  181. Josefson, J. L., Listernick, R., Charrow, J. & Habiby, R. L. Growth hormone excess in children with optic pathway tumors is a transient phenomenon. Horm. Res. Paediatr. 86, 35–38 (2016).

    CAS  PubMed  Google Scholar 

  182. Melmed, S. et al. Guidelines for acromegaly management: an update. J. Clin. Endocrinol. Metab. 94, 1509–1517 (2009).

    CAS  PubMed  Google Scholar 

  183. Katznelson, L. et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly — 2011 update: executive summary. Endocr. Pr. 17 (Suppl. 4), 1–44 (2011).

    Google Scholar 

  184. Ezzat, S. et al. Canadian consensus guidelines for the diagnosis and management of acromegaly. Clin. Invest. Med. 29, 29–39 (2006).

    CAS  PubMed  Google Scholar 

  185. Hindmarsh, P. C., Pringle, P. J., Stanhope, R. & Brook, C. G. The effect of a continuous infusion of a somatostatin analogue (octreotide) for two years on growth hormone secretion and height prediction in tall children. Clin. Endocrinol. (Oxf.) 42, 509–515 (1995).

    CAS  Google Scholar 

  186. Hindmarsh, P. C., Pringle, P. J., Di Silvio, L. & Brook, C. G. A preliminary report on the role of somatostatin analogue (SMS 201–995) in the management of children with tall stature. Clin. Endocrinol. (Oxf.) 32, 83–91 (1990).

    CAS  Google Scholar 

  187. Goldenberg, N. et al. Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant. J. Clin. Endocrinol. Metab. 93, 2953–2956 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Daniel, A., d’Emden, M. & Duncan, E. Pituitary gigantism treated successfully with the growth hormone receptor antagonist, pegvisomant. Intern. Med. J. 43, 345–347 (2013).

    CAS  PubMed  Google Scholar 

  189. Creo, A. L. & Lteif, A. N. Pituitary gigantism: a retrospective case series. J. Pediatr. Endocrinol. Metab. 29, 597–602 (2016).

    PubMed  Google Scholar 

  190. Maheshwari, H. G. et al. Long-acting peptidomimergic control of gigantism caused by pituitary acidophilic stem cell adenoma. J. Clin. Endocrinol. Metab. 85, 3409–3416 (2000).

    CAS  PubMed  Google Scholar 

  191. Müssig, K. et al. Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma. Exp. Clin. Endocrinol. Diabetes 115, 198–202 (2007).

    PubMed  Google Scholar 

  192. Rix, M., Laurberg, P., Hoejberg, A. S. & Brock-Jacobsen, B. Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl. Eur. J. Endocrinol. 153, 195–201 (2005).

    CAS  PubMed  Google Scholar 

  193. Mangupli, R. et al. Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening. Pituitary 19, 507–514 (2016).

    CAS  PubMed  Google Scholar 

  194. Franck, S. E. et al. A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues. Eur. J. Endocrinol. 176, 421–430 (2017).

    CAS  PubMed  Google Scholar 

  195. Neggers, S. J. & van der Lely, A. J. Combination treatment with somatostatin analogues and pegvisomant in acromegaly. Growth Horm. IGF Res. 21, 129–133 (2011).

    CAS  PubMed  Google Scholar 

  196. Trainer, P. J. et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N. Engl. J. Med. 342, 1171–1177 (2000).

    CAS  PubMed  Google Scholar 

  197. Bernabeu, I. et al. Pegvisomant and cabergoline combination therapy in acromegaly. Pituitary 16, 101–108 (2013).

    CAS  PubMed  Google Scholar 

  198. Personnier, C. 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. 75, 392–402 (2011).

    CAS  PubMed  Google Scholar 

  199. Daly, A. et al. X-Linked acro-gigantism (X-LAG) syndrome: two new cases with long-term follow-up [abstract]. 4th ENEA Workshop https://orbi.uliege.be/handle/2268/189337 (2015).

  200. Petrossians, P. et al. Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs. Eur. J. Endocrinol. 152, 61–66 (2005).

    CAS  PubMed  Google Scholar 

  201. Saldarriaga, C. et al. Postoperative diabetes insipidus and hyponatremia in children after transsphenoidal surgery for adrenocorticotropin hormone and growth hormone secreting adenomas. J. Pediatr. 195, 169–174 (2018).

    PubMed  Google Scholar 

  202. Hindmarsh, P. C. Long-term follow-up after bilateral percutaneous epiphysiodesis around the knee to reduce excessive predicted final height. Arch. Dis. Child. 103, 207–208 (2018). This article presents an expert assessment of the challenges of epiphysiodesis and outcomes in tall stature.

    PubMed  Google Scholar 

  203. Edouard, T. What treatment for a child with tall stature? Ann. Endocrinol. (Paris) 78, 104–105 (2017).

    Google Scholar 

  204. Odink, R. J. et al. Reduction of excessive height in boys by bilateral percutaneous epiphysiodesis around the knee. Eur. J. Pediatr. 165, 50–54 (2006).

    PubMed  Google Scholar 

  205. Benyi, E. et al. Efficacy and safety of percutaneous epiphysiodesis operation around the knee to reduce adult height in extremely tall adolescent girls and boys. Int. J. Pediatr. Endocrinol. 2010, 740629 (2010).

    PubMed  PubMed Central  Google Scholar 

  206. Goedegebuure, W. J. et al. Long-term follow-up after bilateral percutaneous epiphysiodesis around the knee to reduce excessive predicted final height. Arch. Dis. Child. 103, 219–223 (2018).

    PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge the support of an Actions de Recherche Concertées 2017 grant for the GOLIATHS project from Liège Université, a Fonds d’Investissement pour la Recherche Scientifique grant from the Centre Hospitalier Universitaire de Liège and a grant from the Jabbs Foundation, UK.

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Nature Reviews Endocrinology thanks K. Kovacs, S. Cannavò and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Endocrinology, Centre Hospitalier Universitaire de Liège, Liège Université, Liège, Belgium

    Albert Beckers, Patrick Petrossians & Adrian F. Daly

  2. Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases and Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines, Liège Université, Liège, Belgium

    Julien Hanson

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A.B. and A.F.D. researched the data for the article, contributed to the discussion of content, wrote the article and reviewed and edited the manuscript before submission. P.P. and J.H. researched data for the article and reviewed and/or edited the article before submission.

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Glossary

Somatotropic axis

The hormonal system, including the hypothalamus, pituitary and peripheral tissues, that controls growth hormone secretion from the anterior pituitary gland and insulin-like growth factor 1 mainly from the liver.

Somatotrope adenoma

A benign tumour of the growth hormone-producing cells of the anterior pituitary gland.

Epiphyses

Proximal and distal end portions of long bones that contain cartilaginous growth plates at which longitudinal bone growth occurs until growth plate closure and epiphyseal fusion with the rest of the bone.

Extrasellar extension

Growth of a pituitary adenoma outside of the borders of the sella turcica.

Haploblock

Also known as haplotype block. A set of neighbouring genetic alleles or markers that tend to be inherited together over generations.

Pneumatization

Development of an air space within a sinus, such as the sphenoid sinus, that gradually takes place over childhood and has an influence on the neurosurgical access to the anterior pituitary gland.

Transsphenoidal

Neurosurgical approach to access the pituitary gland in the sella turcica via the sphenoid sinus.

Sellar floor

The base of the sella turcica in which the pituitary gland lies.

Transfrontal approach

A neurosurgical approach to the pituitary gland via the frontal bone of the skull.

Tumour debulking

Removal of tumour tissue to reduce overall tumour size and related symptoms when full tumour resection cannot be performed.

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Beckers, A., Petrossians, P., Hanson, J. et al. The causes and consequences of pituitary gigantism. Nat Rev Endocrinol 14, 705–720 (2018). https://doi.org/10.1038/s41574-018-0114-1

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